Acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same

ABSTRACT

The present invention relates to an acyclic nucleoside phosphonate derivative which is useful as an antiviral agent (particularly, against hepatitis B virus), pharmaceutically acceptable salts, stereoisomers, and a process for the preparation thereof.

This Application is a Divisional of application Ser. No. 11/455,679,filed on Jun. 20, 2006, now U.S. Pat. No. 7,605,147 which is acontinuation-in-part (CIP) of U.S. application Ser. No. 10/450,780,filed Jun. 18, 2003 now U.S. Pat. No. 7,157,448, which application Ser.No. 10/450,780 is the U.S. National Phase of PCT InternationalApplication No. PCT/KR2002/00086 filed on Jan. 18, 2002 under 35 U.S.C.§371. Priority is also claimed to Korean Application No. 2001-3087 filedon Jan. 19, 2001 in Korea. The entire contents of each of theabove-identified applications are hereby incorporated by reference.

TECHNICAL FIELD

The present invention relates to an acyclic nucleoside phosphonatederivative represented by the following formula (1):

in which

-    represents single bond or double bond,-   R¹, R², R³, R⁷ and R⁸ independently of one another represent    hydrogen, halogen, hydroxy, amino, C₁-C₇-alkyl, C₂-C₆-alkenyl,    C₁-C₅-alkylamino, C₁-C₅-aminoalkyl, or C₁-C₅-alkoxy,-   R⁴ and R⁵ independently of one another represent hydrogen, or    represent C₁-C₄-alkyl optionally substituted by one or more    substituents selected from the group consisting of halogen    (particularly, fluorine), C₁-C₄-alkoxy, phenoxy, C₇-C₁₀-phenylalkoxy    and C₂-C₅-acyloxy, or represent C₁-C₇-acyl, C₆-C₁₂-aryl or    optionally substituted carbamoyl, or represent —(CH₂)m-OC(═O)—R⁶    wherein m denotes an integer of 1 to 12 and R⁶ represents    C₁-C₁₂-alkyl, C₂-C₇-alkenyl, C₁-C₅-alkoxy, C₁-C₇-alkylamino,    di(C₁-C₇-alkyl)amino, C₃-C₆-cycloalkyl, or 3 to 6-membered    heterocycle having 1 or 2 hetero atoms selected from a group    consisting of nitrogen and oxygen,-   Y represents —O—, —S—, —CH(Z)—, ═C(Z)—, —N(Z)—, ═N—, —SiH(Z)—, or    =Si(Z)—, wherein Z represents hydrogen, hydroxy or halogen, or    represents C₁-C₇-alkyl, C₁-C₅-alkoxy, allyl, hydroxy-C₁-C₇-alkyl,    C₁-C₇-aminoalkyl or phenyl,-   Q represents a group having the following formula:

wherein

-   X¹, X², X³ and X⁴ independently of one another represent hydrogen,    amino, hydroxy or halogen, or represent C₁-C₇-alkyl, C₁-C₅-alkoxy,    allyl, hydroxy-C₁-C₇-alkyl, phenyl or phenoxy each of which is    optionally substituted by nitro or C₁-C₅-alkoxy, or represent    C₆-C₁₀-arylthio which is optionally substituted by nitro, amino,    C₁-C₆-alkyl or C₁-C₄-alkoxy, or represent C₆-C₁₂-arylamino,    C₁-C₇-alkylamino, di(C₁-C₇-alkyl)amino, C₃-C₆-cycloalkylamino or a    structure of

wherein n denotes an integer of 1 or 2 and Y¹ represents O, CH₂ or N—R(R represents C₁-C₇-alkyl or C₆-C₁₂-aryl),which is useful as an antiviral agent (particularly, against hepatitis Bvirus), pharmaceutically acceptable salts, stereoisomers, and a processfor the preparation thereof.

BACKGROUND ART

Purine or pyrimidine derivatives have anti-cancer and antiviralactivities, and more than 10 kinds of the compounds including AZT, 3TCand ACV have already been commercialized. Particularly, since acyclicnucleoside phosphonate derivatives show a potent antiviral effect,cidopovir has been commercialized as an antiviral agent and manycompounds including PMEA and PMPA now entered into the step of clinicaltrials. However, the earlier developed compounds were not perfect in theaspects of toxicity or pharmaceutical activity, and thus, it is stilldesired to develop a compound having no toxicity as well as a superioractivity. The prior researches for purine or pyrimidine derivatives oracyclic nucleoside phosphonate derivatives as reported heretofore are asfollows. Patents: U.S. Pat. No. 5,817,647; U.S. Pat. No. 5,977,061; U.S.Pat. No. 5,886,179; U.S. Pat. No. 5,837,871; U.S. Pat. No. 6,069,249; WO99/09031; WO96/09307; WO95/22330; U.S. Pat. No. 5,935,946; U.S. Pat. No.5,877,166; U.S. Pat. No. 5,792,756; Journals: International Journal ofAntimicrobial Agents 12 (1999), 81-95; Nature 323 (1986), 464;Heterocycles 31(1990), 1571; J. Med. Chem. 42 (1999), 2064; Pharmacology& Therapeutics 85 (2000), 251; Antiviral Chemistry & Chemotherapy 5(1994), 57-63; Bioorganic & Medicinal Chemistry Letters 10 (2000)2687-2690; Biochemical Pharmacology 60 (2000), 1907-1913; AntiviralChemistry & Chemotherapy 8 (1997) 557-564; Antimicrobial Agent andChemotherapy 42 (1999) 2885-2892.

DISCLOSURE OF INVENTION

Thus, the present inventors extensively studied to develop a compoundhaving a superior biological activity (pharmaceutical effect) to as wellas a lower toxicity than the existing acyclic nucleoside phosphonatescommercialized or entered into the step of clinical trials. As a result,we found that the above compound of formula (1) characterized by itsunique chemical structure exhibits a potent pharmaceutical activity, andthen completed the present invention.

Therefore, one object of the present invention is to provide thecompound of formula (1) having a good use of antiviral agent,pharmaceutically acceptable salts or isomers thereof.

It is another object of the present invention to provide a process forthe preparation of the compound of formula (1).

It is still another object of the present invention to provideintermediates which are advantageously used for the preparation of thecompound of formula (1).

BEST MODE FOR CARRYING OUT THE INVENTION

The compound of formula (1) according to the present invention, asrepresented below, is a type of acyclic nucleoside phosphonatederivative having a natural base, such as for example, adenine, guanine,uracil, cytosine, thymine or derivatives thereof:

in which

-    represents single bond or double bond,-   R¹, R², R³, R⁷ and R⁸ independently of one another represent    hydrogen, halogen, hydroxy, amino, C₁-C₇-alkyl, C₂-C₆-alkenyl,    C₁-C₅-alkylamino, C₁-C₅-aminoalkyl, or C₁-C₅-alkoxy,-   R⁴ and R⁵ independently of one another represent hydrogen, or    represent C₁-C₄-alkyl optionally substituted by one or more    substituents selected from the group consisting of halogen    (particularly, fluorine), C₁-C₄-alkoxy, phenoxy, C₇-C₁₀-phenylalkoxy    and C₂-C₅-acyloxy, or represent C₁-C₇-acyl, C₆-C₁₂-aryl or    optionally substituted carbamoyl, or represent —(CH₂)m-OC(═O)—R⁶    wherein m denotes an integer of 1 to 12 and R⁶ represents    C₁-C₁₂-alkyl, C₂-C₇-alkenyl, C₁-C₅-alkoxy, C₁-C₇-alkylamino,    di(C₁-C₇-alkyl)amino, C₃-C₆-cycloalkyl, or 3 to 6-membered    heterocycle having 1 or 2 hetero atoms selected from a group    consisting of nitrogen and oxygen,-   Y represents —O—, —S—, —CH(Z)—, ═C(Z)—, —N(Z)—, ═N—, —SiH(Z)—, or    ═Si(Z)—, wherein Z represents hydrogen, hydroxy or halogen, or    represents C₁-C₇-alkyl, C₁-C₅-alkoxy, allyl, hydroxy-C₁-C₇-alkyl,    C₁-C₇-aminoalkyl or phenyl,-   Q represents a group having the following formula:

wherein

-   X¹, X², X³ and X⁴ independently of one another represent hydrogen,    amino, hydroxy or halogen, or represent C₁-C₇-alkyl, C₁-C₅-alkoxy,    allyl, hydroxy-C₁-C₇-alkyl, phenyl or phenoxy each of which is    optionally substituted by nitro or C₁-C₅-alkoxy, or represent    C₆-C₁₀-arylthio which is optionally substituted by nitro, amino,    C₁-C₆-alkyl or C₁-C₄-alkoxy, or represent C₆-C₁₂-arylamino,    C₁-C₇-alkylamino, di(C₁-C₇-alkyl)amino, C₃-C₆-cycloalkylamino or a    structure of

wherein n denotes an integer of 1 or 2 and Y¹ represents O, CH₂ or N—R(R represents C₁-C₇-alkyl or C₆-C₁₂-aryl).

Since the compound of formula (1) according to the present invention mayhave one or more asymmetric carbon atoms in the structure depending onthe kind of substituents, it can be present in the form of theindividual enantiomers, diastereomers, or mixtures thereof includingracemate. Further, when a double bond is included in the structure, itcan be present in the form of E or Z isomer. Thus, the present inventionalso includes all of these isomers and their mixtures.

Also, the compound of formula (1) according to the present invention canform a pharmaceutically acceptable salt. Such salt includes non-toxicacid addition salt containing pharmaceutically acceptable anion, forexample a salt with inorganic acids such as hydrochloric acid, sulfuricacid, nitric acid, phosphoric acid, hydrobromic acid, hydriodic acid,etc., a salt with organic carboxylic acids such as tartaric acid, formicacid, citric acid, acetic acid, trichloroacetic acid, trifluoroaceticacid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleicacid, etc., or a salt with sulfonic acids such as methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid,etc., particularly preferably with sulfuric acid, methanesulfonic acidor hydrohalic acid, etc.

Among the compound of formula (1) showing a potent pharmaceuticalactivity, the preferred compounds are those wherein

-    represents single bond,-   R¹, R², R³, R⁷ and R⁸ independently of one another represent    hydrogen, fluorine, hydroxy, C₁-C₇-alkyl, C₂-C₆-alkenyl,    C₁-C₅-alkylamino, C₁-C₅-aminoalkyl, or C₁-C₅-alkoxy,-   R⁴ and R⁵ independently of one another represent hydrogen, or    represent C₁-C₄-alkyl optionally substituted by one or more    substituents selected from the group consisting of fluorine,    C₁-C₄-alkoxy and phenoxy, or represent carbamoyl substituted by    C₁-C₅-alkyl, or represent —(CH₂)m-OC(═O)—R⁶ wherein m denotes an    integer of 1 to 12 and R⁶ represents C₁-C₁₂-alkyl, C₂-C₇-alkenyl,    C₁-C₅-alkoxy, C₁-C₇-alkylamino, di(C₁-C₇-alkyl)amino,    C₃-C₆-cycloalkyl, or 3 to 6-membered heterocycle having 1 or 2    hetero atoms selected from a group consisting of nitrogen and    oxygen,-   Y represents —O—, —S—, or —N(Z)—, wherein Z represents hydrogen,    hydroxy, C₁-C₇-alkyl, or hydroxy-C₁-C₇-alkyl,-   Q represents a group having the following formula:

wherein

-   X¹ represents hydrogen, amino, hydroxy or halogen, or represents    C₁-C₇-alkyl, C₁-C₅-alkoxy, hydroxy-C₁-C₇-alkyl or phenoxy each of    which is optionally substituted by nitro or C₁-C₅-alkoxy, or    represents C₆-C₁₀-arylthio which is optionally substituted by nitro,    amino, C₁-C₆-alkyl or C₁-C₄-alkoxy, or represents C₆-C₁₂-arylamino,    C₁-C₇-alkylamino, di(C₁-C₇-alkyl)amino, C₃-C₆-cycloalkylamino or a    structure of

wherein n denotes an integer of 1 or 2 and Y¹ represents O, CH₂ or N—R(R represents C₁-C₇-alkyl), and

-   X², X³ and X⁴ independently of one another represent hydrogen,    amino, hydroxy, halogen, C₁-C₇-alkyl, C₁-C₅-alkoxy, or    C₁-C₇-alkylamino.

Most preferred compounds are those wherein

 represents single bond, R¹, R³, R⁷ and R⁸ independently of one anotherrepresent hydrogen, R² represents hydrogen or methyl, R⁴ and R⁵independently of one another represent t-butylcarbonyloxymethyl,isopropoxycarbonyloxymethyl or 2,2,2-trifluoroethyl, Y represents —O—, Qrepresents

wherein X¹ represents hydrogen, hydroxy, ethoxy, 4-methoxyphenylthio or4-nitrophenylthio, and X² represents amino.

Typical examples of the compound of formula (1) according to the presentinvention are described in the following Tables 1 and 7.

TABLE 1 COM. NO. STRUCTURE 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

TABLE 2

COM. NO. X¹ X² R⁴ R⁵ 45 OH NH₂ CH₂CF₃ CH₂CF₃ 46 Cl NH₂ CH₂CF₃ CH₂CF₃ 47NH₂ NH₂ CH₂CF₃ CH₂CF₃ 48 NH₂ H CH₂CF₃ CH₂CF₃ 49 H NH₂ CH₂CF₃ CH₂CF₃ 50

NH₂ CH₂CF₃ CH₂CF₃ 51 NHC₂H₅ NH₂ CH₂CF₃ CH₂CF₃ 52 N(CH₃)₂ NH₂ CH₂CF₃CH₂CF₃ 53

NH₂ CH₂CF₃ CH₂CF₃ 54 OCH₃ NH₂ CH₂CF₃ CH₂CF₃ 55 CH₃ NH₂ CH₂CF₃ CH₂CF₃ 56C₂H₅ NH₂ CH₂CF₃ CH₂CF₃ 57

NH₂ CH₂CF₃ CH₂CF₃ 58

NH₂ CH₂CF₃ CH₂CF₃ 59

NH₂ CH₂CF₃ CH₂CF₃ 60

NH₂ CH₂CF₃ CH₂CF₃ 61

NH₂ CH₂CF₃ CH₂CF₃ 62

NH₂ CH₂CF₃ CH₂CF₃ 63

NH₂ CH₂CF₃ CH₂CF₃ 64

NH₂ CH₂CF₃ CH₂CF₃ 65

NH₂ H H 66

NH₂ H H 67

NH₂ H H 68

NH₂

69 H NH₂

70 H NH₂

71 H NH₂

72 H NH₂

73 H NH₂

74 H NH₂

75 H NH₂

76 H NH₂

77 H NH₂

78 H NH₂

79

NH₂

80 H NH₂

81 H NH₂

82 H NH₂

83 OH NH₂

84 OH NH₂

85

NH₂

86 OH NH₂

87

NH₂

88

NH₂

89 NH₂ H

90 NH₂ H

91 NH₂ H

92

NH₂

93

NH₂

94 NH₂ H H H 95

NH₂ H H 96

NH₂ H H

TABLE 3

COM. NO. X¹ X² R⁴ R⁵ 97 OH NH₂ H H 98 H NH₂ H H 99

NH₂ H H 100

NH₂ H H 101

NH₂ H H 102 NH₂ NH₂ H H 103 NH₂ H H H 104 OH H H H 105 OH NH₂

106 H NH₂

107 NH₂ H

108

NH₂

109 OH NH₂

110 H NH₂

111 NH₂ H

112

NH₂

113

NH₂

114

NH₂ CH₂CF₃ CH₂CF₃ 115

NH₂ CH₂CF₃ CH₂CF₃ 116

NH₂

117

NH₂

118

NH₂

TABLE 4

COM. NO. Z X¹ X² R⁴ R⁵ 119 H OH NH₂ H H 120 H H NH₂ H H 121 H NH₂ H H H122 CH₃ OH NH₂ H H 123 CH₃ H NH₂ H H 124 CH₃ NH₂ H H H 125 C₂H₅ NH₂ H HH 126 CH₃ NH₂ H

127 CH₃ NH₂ H

128 C₂H₅ H NH₂

129 C₂H₅ H NH₂

TABLE 5

COM. NO. Z X¹ X² R⁴ R⁵ 130 H OH NH₂ H H 131 H H NH₂ H H 132 H NH₂ H H H133 H OH NH₂

134 H NH₂ H

135 CH₃ OH NH₂ H H 136 CH₃ H NH₂ H H 137 CH₃ NH₂ H H H

TABLE 6

COM. NO. Z X¹ X² R⁴ R⁵ 138 H OH NH₂ H H 139 H H NH₂ H H 140 H NH₂ H H H141 H

NH₂ H H 142 CH₃ OH NH₂ H H 143 CH₃ NH₂ H H H 144 CH₃ H NH₂ H H 145 CH₃NH₂ H

TABLE 7

COM. NO. X¹ X² R⁴ R⁵ 146 OH NH₂ H H 147 H NH₂ H H 148 NH₂ H H H 149 OHNH₂

150 H NH₂

151 NH₂ H

152 NH₂ H

153 OH NH₂

More particularly preferable compounds among the compounds described inthe above Tables 1 and 7 are as follows:

-   ({1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic    acid (Compound 1);-   3-[({1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 2);-   ({1-[(2-amino-6-chloro-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic    acid (Compound 3);-   3-[({1-[(2-amino-6-chloro-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 4);-   ({1-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic    acid (Compound 5);-   3-[({1-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 6);-   ({1-[(2-amino-6-fluoro-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic    acid (Compound 7);-   3-[({1-[(2-amino-6-fluoro-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 8);-   ({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic    acid (Compound 9);-   3-[({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 10);-   ({1[(2-amino-6-cyclopropylamino-9H-purin-9-yl)methyl]cyclopropyl}oxy)meth-ylphosphonic    acid (Compound 11);-   3-[({1-[(2-amino-6-cyclopropylamino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 12);-   [(1-{[2-amino-6-(dimethylamino)-9H-purin-9-yl]methyl}cyclopropyl)oxy]methylphosphonic    acid (Compound 15);-   3-{[(1-{[2-amino-6-(dimethylamino)-9H-purin-9-yl]methyl}cyclopropyl)oxy]methyl}-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 16);-   [(1-{[2-amino-6-(isopropylamino)-9H-purin-9-yl]methyl}cyclopropyl)oxy]methylphosphonic    acid (Compound 17);-   3-{[(1-{[2-amino-6-(isopropylamino)-9H-purin-9-yl]methyl}cyclopropyl)oxy]methyl}-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 18);-   ({1-[(2,6-diamino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic    acid (Compound 19);-   3-[({1-[(2,6-diamino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 20);-   ({1-[(2-amino-6-methoxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic    acid (Compound 21);-   3-[({1-[(2-amino-6-methoxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 22);-   ({1-[(2-amino-6-ethoxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic    acid (Compound 23);-   3-[({1-[(2-amino-6-ethoxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 24);-   ({1-[(2-amino-6-methyl-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic    acid (Compound 25);-   3-[({1-[(2-amino-6-methyl-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 26);-   [(1-{[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]methyl}cyclopropyl)oxy]methylphosphonic    acid (Compound 31);-   8,8-dimethyl-3-{[(1-{[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]methyl}cyclopropyl)oxy]methyl}-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 32);-   [(1-{[2-amino-6-(4-morpholinyl)-9H-purin-9-yl]methyl}cyclopropyl)oxy]methylphosphonic    acid (Compound 37);-   3-{[(1-{[2-amino-6-(4-morpholinyl)-9H-purin-9-yl]methyl}cyclopropyl)oxy]met-hyl}-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 38);-   bis(2,2,2-trifluoroethyl)({1-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate    (Compound 45);-   bis(2,2,2-trifluoroethyl)({1-[(2-amino-6-chloro-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate    (Compound 46);-   bis(2,2,2-trifluoroethyl)({1-[(2,6-diamino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate    (Compound 47);-   bis(2,2,2-trifluoroethyl)({1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate    (Compound 48);-   bis(2,2,2-trifluoroethyl)({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate    (Compound 49);-   bis(2,2,2-trifluoroethyl)({1-[(2-amino-6-dimethylamino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate    (Compound 52);-   bis(2,2,2-trifluoroethyl)({1-[(2-amino-6-isopropylamino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate    (Compound 53);-   bis(2,2,2-trifluoroethyl)({1-[(2-amino-6-methoxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate    (Compound 54);-   bis(2,2,2-trifluoroethyl)[(1-{[2-amino-6-(4-morpholinyl)-9H-purin-9-yl]methyl}cyclopropyl)oxy]methylphosphonate    (Compound 58);-   bis(2,2,2-trifluoroethyl)[(1-{[2-amino-6-(phenylsulfanyl)-9H-purin-9-yl]methyl}cyclopropyl)oxy]methylphosphonate    (Compound 61);-   bis(2,2,2-trifluoroethyl){[1-({2-amino-6-[(4-methylphenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonate    (Compound 62);-   bis(2,2,2-trifluoroethyl){[1-({2-amino-6-[(4-methoxyphenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonate    (Compound 63);-   bis(2,2,2-trifluoroethyl){[1-({2-amino-6-[(4-nitrophenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonate    (Compound 64);-   [(1-{[2-amino-6-(phenylsulfanyl)-9H-purin-9-yl]methyl}cyclopropyl)oxy]methylphosphonic    acid (Compound 65);-   {[1-({2-amino-6-[(4-methylphenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonic    acid (Compound 66);-   3-({[1-({2-amino-6-[(4-methylphenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 68);-   bis{[(t-butoxycarbonyl)oxy]methyl}({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate    (Compound 69);-   bis{[(isopropoxycarbonyl)oxy]methyl}({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate    (Compound 70);-   bis{[(ethoxycarbonyl)oxy]methyl}({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate    (Compound 71);-   bis{[(isobutoxycarbonyl)oxy]methyl}({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate    (Compound 72);-   3-[({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-9-methyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphadec-1-yl    3-methylbutanoate (Compound 74);-   3-[({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8-methyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    2-methylpropanoate (Compound 78);-   3-({[1-({2-amino-6-[(4-methoxyphenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclo    propyl]oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 79);-   3-[({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-3,7-dioxo-7-(1-pyrrolidinyl)-2,4,6-trioxa-38⁵-phosphahept-1-yl    1-pyrrolidinecarboxylate (Compound 80);-   3-[({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-3,7-dioxo-7-(1-piperidinyl)-2,4,6-trioxa-38⁵-phosphahept-1-yl    1-piperidinecarboxylate (Compound 81);-   3-[({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-7-(4-morpholinyl)-3,7-dioxo-2,4,6-trioxa-38⁵-phosphahept-1-yl    4-morpholinecarboxylate (Compound 82);-   bis{[(t-butoxycarbonyl)oxy]methyl}[(1-{[2-amino-6-hydroxy-9H-purin-9-yl]methyl}cyclopropyl)oxy]methylphosphonate    (Compound 83);-   bis{[(isopropoxycarbonyl)oxy]methyl}[(1-{[2-amino-6-hydroxy-9H-purin-9-yl]methyl}cyclopropyl)oxy]methylphosphonate    (Compound 84);-   bis{[(isopropoxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonate    (Compound 85);-   3-[({1-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-7-cyclopentyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphahept-1-yl    cyclopentanecarboxylate (Compound 86);-   3-({[1-({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 87);-   bis{[(isopropoxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonate    (Compound 88);-   bis{[(isopropoxycarbonyl)oxy]methyl}({1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate    (Compound 89);-   3-[({1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-9-methyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphadec-1-yl    3-methylbutanoate (Compound 90);-   3-[({1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-7-cyclopentyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphahept-1-yl    cyclopentanecarboxylate (Compound 91);-   bis{[(t-butoxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonate    (Compound 92);-   bis{[(t-butoxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonate    (Compound 93);-   {[1-({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonic    acid (Compound 95);-   {[1-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonic    acid (Compound 96);-   ({1-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonic    acid (Compound 97);-   ({1-[(2-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonic    acid (Compound 98);-   {[1-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-9H-purin-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonic    acid (Compound 99);-   {[1-({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purin-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonic    acid (Compound 100);-   {[1-({2-amino-[6-(4-methylphenyl)sulfanyl]-9H-purin-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonic    acid (Compound 101);-   ({1-[(2,6-diamino-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonic    acid (Compound 102);-   ({1-[(6-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonic    acid (Compound 103);-   3-[({1-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 105);-   3-[({1-[(2-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 106);-   3-[({1-[(6-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 107);-   3-({[1-({2-amino-6-[(4-methoxyphenyl)sulfanyl]-9H-purin-9-yl}methyl)-2-methylcyclopropyl]oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 108);-   bis{[(isopropoxycarbonyl)oxy]methyl}[(1-{[2-amino-6-hydroxy-9H-purin-9-yl]methyl}-2-methylcyclopropyl)oxy]methylphosphonate    (Compound 109);-   bis{[(isopropoxycarbonyl)oxy]methyl}({1-[(2-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonate    (Compound 110);-   bis{[(isopropoxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-9H-purin-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate    (Compound 112);-   bis{[(t-butoxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-9H-purin-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate    (Compound 113);-   bis(2,2,2-trifluoroethyl){[1-({2-amino-6-[(4-methoxyphenyl)sulfanyl]-9H-purin-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate    (Compound 114);-   bis(2,2,2-trifluoroethyl){[1-({2-amino-6-[(4-nitrophenyl)sulfanyl]-9H-purin-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate    (Compound 115);-   bis{[(t-butoxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purin-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate    (Compound 116);-   bis{[(isopropoxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purin-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate    (Compound 117);-   3-({[1-({2-amino-6-[(4-nitrophenyl)sulfanyl]-9H-purin-9-yl}methyl)-2-methylcyclopropyl]oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 118);-   ({1-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl}amino)methylphosphonic    acid (Compound 119);-   ({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}amino)methylphosphonic    acid (Compound 120);-   ({1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}amino)methylphosphonic    acid (Compound 121);-   [{1-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl}(methyl)amino]methylphosphonic    acid (Compound 122);-   [{1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}(ethyl)amino]methylphosphonic    acid (Compound 125);-   3-{[{(1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl)(methyl)amino)methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 126);-   bis{[(isopropoxycarbonyl)oxy]methyl}[{1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}(methyl)amino]methylphosphonate    (Compound 127);-   3-{[{1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}(ethyl)amino]methyl}-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 129);-   (E)-2-{1-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl}ethenylphosphonic    acid (Compound 130);-   (E)-2-{1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}ethenylphosphonic    acid (Compound 131);-   (E)-2-{1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}ethenylphosphonic    acid (Compound 132);-   3-((E)-2-{1-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl}ethenyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 133);-   3-((E)-2-{1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}ethenyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 134);-   (E)-2-{1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}-1-propenylphosphonic    acid (Compound 137);-   2-{1-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl}ethylphosphonic    acid (Compound 138);-   2-{1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}ethylphosphonic acid    (Compound 139);-   2-{1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}ethylphosphonic acid    (Compound 140);-   2-[1-({2-amino-6-[(4-methylphenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]ethylphosphonic    acid (Compound 141);-   2-{1-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl}propylphosphonic    acid (Compound 142);-   2-{1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}propylphosphonic    acid (Compound 143);-   2-{1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}propylphosphonic    acid (Compound 144);-   3-(2-{1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}propyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 145);-   ({1-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]-2,2-dimethylcyclopropyl}oxy)methylphosphonic    acid (Compound 146);-   ({1-[(2-amino-9H-purin-9-yl)methyl]-2,2-dimethylcyclopropyl}oxy)methylphosphonic    acid (Compound 147);-   ({1-[(6-amino-9H-purin-9-yl)methyl]-2,2-dimethylcyclopropyl}oxy)methylphosphonic    acid (Compound 148);-   3-[({1-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]-2,2-dimethylcyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 149);-   3-[({1-[(2-amino-9H-purin-9-yl)methyl]-2,2-dimethylcyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 150);-   3-[({1-[(6-amino-9H-purin-9-yl)methyl]-2,2-dimethylcyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl    pivalate (Compound 151);-   bis{[(isopropoxycarbonyl)oxy]methyl}({1-[(6-amino-9H-purin-9-yl)methyl]-2,2-dimethylcyclopropyl}oxy)methylphosphonate    (Compound 152); and-   bis{[(isopropoxycarbonyl)oxy]methyl}[(1-{[2-amino-6-hydroxy-9H-purin-9-yl]methyl}-2,2-dimethylcyclopropyl)oxy]methylphosphonate    (Compound 153).

The compound of formula (1) according to the present invention can beprepared by a process as explained below, and thus, it is another objectof the present invention to provide such a preparation process. However,conditions of the process, such as for example, reactants, solvents,bases, amounts of the reactants used, etc. are not restricted to thoseexplained below. The compound of the present invention may also beconveniently prepared by optionally combining the various synthetic waysdescribed in the present specification or known in the arts, and such acombination can be easily performed by one of ordinary skill in the artto which the present invention pertains.

The compound of formula (1) of the present invention can be preparedcharacterized in that

(a) a compound represented by the following formula (2):

in which R¹, R², R³, R⁴, R⁵, R⁷, R⁸ and Y are defined as previouslydescribed, and L represents a leaving group, preferablymethanesulfonyloxy, p-toluenesulfonyloxy or halogen, is reacted with acompound represented by the following formula (3):QH  (3)in which Q is defined as previously described, to produce the compoundof formula (1),

(b) a compound represented by the following formula (9):

in which R¹, R², R³, R⁷, R⁸, Y and L are defined as previouslydescribed, and R⁹ and R¹⁰ independently of one another representoptionally substituted alkyl, is reacted with the compound of formula(3) to produce a compound represented by the following formula (10):

in which R¹, R², R³, R⁷, R⁸, Y, Q, R⁹ and R¹⁰ are defined as previouslydescribed, and the resulting compound of formula (10) is hydrolyzed inthe presence of a Lewis acid to produce a compound represented by thefollowing formula (1a):

in which R¹, R², R³, R⁷, R⁸, Y and Q are defined as previouslydescribed, or

(c) groups R^(4′) and R^(5′) are introduced into the compound of formula(1a) to produce a compound represented by the following formula (1b):

in which R¹, R², R³, R⁷, R⁸, Y and Q are defined as previouslydescribed, and R^(4′) and R^(5′) represent R⁴ and R⁵ with the exceptionof hydrogen, respectively, or further the compounds thus obtained aresubjected to conventional conversions (see: U.S. Pat. Nos. 6,037,335,5,935,946, and 5,792,756).

In the above process variants (a) to (c) for preparing the compound offormula (1), the reactions may be carried out in a solvent and in thepresence of a base. As the solvent, one or more selected from a groupconsisting of dimethylformamide, dichloromethane, tetrahydrofuran,chloroform, 1-methyl-2-pyrrolidinone and dimethylacetamide can bementioned, and as the base one or more selected from a group consistingof sodium hydride, sodium carbonate, potassium carbonate, sodiumbicarbonate, potassium bicarbonate, potassium t-butoxide, hydrogenbis(trimethylsilyl)amide, sodium amide, cesium carbonate and potassiumbis(trimethylsilyl)amide can be mentioned. The Lewis acid which can beused in the process variant (b) includes trimethylsilylhalide. Further,in the process variant (c) for introducing the groups R^(4′) and R^(5′)into the compound of formula (1a), this compound is subjected to anether-forming reaction with an alkylhalide in the presence of a base, oris treated with thionyl chloride, oxalyl chloride or phosphoruspentachloride to produce a dichlorophosphonate derivative which is thenreacted with a suitable alcohol or amine to give the desired compound.

The phosphonate compound of formula (2) used as a starting material inthe above process is itself a novel compound. Therefore, it is anotherobject of the present invention to provide the compound of formula (2).

The compound of formula (2) wherein Y is O, R¹ is hydrogen, and each ofR², R³, R⁷ and R⁸ is hydrogen or alkyl, that is, a compound of thefollowing formula (8), can be prepared characterized in that (i) anethylglycolate, the alcohol group of which is protected, represented bythe following formula (4):

in which P¹ represents an alcohol-protecting group, preferably benzyl(Bn), tetrahydropyranyl (THP), t-butyldiphenylsilyl (TBDPS), ort-butyldimethylsilyl (TBDMS), is reacted with ethyl magnesiumbromide[C₂H₅MgBr] or the corresponding alkyl magnesium bromide or alkylmagnesium chloride in the presence of titaniumtetraisopropoxide[Ti(OiPr)₄], (ii) the resulting cyclopropanolrepresented by the following formula (5):

in which P¹ is defined as previously described and each of R^(2′),R^(3′), R^(7′) and R^(8′) represents hydrogen or alkyl, is subjected toan ether-forming reaction in the presence of a base with a compoundrepresented by the following formula (6):

in which L, R⁴ and R⁵ are defined as previously described, to produce aphosphonate compound represented by the following formula (7):

in which P¹, R^(2′), R^(3′), R^(7′), R^(8′), R⁴ and R⁵ are defined aspreviously described, and (iii) the alcohol-protecting group of theresulting compound of formula (7) is removed and a leaving group (L) isintroduced to produce a compound represented by the following formula(8):

in which L, R^(2′), R^(3′), R^(7′), R^(8′), R⁴ and R⁵ are defined aspreviously described.

The process for preparing the simplest compound of formula (8) (that is,all of R^(2′), R^(3′), R^(7′) and R^(8′) are hydrogen) is brieflydepicted in the following Reaction Scheme 1:

The specific reaction conditions of the above process can be referred tothe following Preparations and Examples.

Further, the compound of formula (2) wherein Y is —CH₂—, and each of R¹,R², R³, R⁷ and R⁸ is hydrogen, that is a compound of the followingformula (11):

in which L, R⁴ and R⁵ are defined as previously described, can beprepared by a process as depictd in the following Reaction Scheme 2:

Reaction Scheme 2 is briefly explained below. (i) According to a knownmethod (see: JOC, 1975, Vol. 40, 2969-2970), dialkylmalonate is reactedwith dihaloethane to give malonic acid wherein cyclopropyl group isintroduced into its 2-position. (ii) The malonic acid is reduced to givediol compound, one hydroxy group of which is then protected with asuitable protecting group (P¹ is defined as previously described). Then,the other hydroxy group is oxidized to an aldehyde group. (iii) Theresulting aldehyde compound is reacted withtetraalkylmethylenediphosphonate to give the desired phosphonatecompound. (iv) The phosphonate compound thus obtained is reduced to givea compound having no unsaturated bond, alcohol-protecting group (P¹) isremoved, and a leaving group (L) is introduced to give the compound offormula (11).

Further, the compound of formula (2) wherein Y is —N(CH₃)— and each ofR¹, R², R³, R⁷ and R⁸ is hydrogen, that is a compound of the followingformula (12):

in which L, R⁴ and R⁵ are defined as previously described, can beprepared by a process as depictd in the following Reaction Scheme 3:

Reaction Scheme 3 is briefly explained below. (i) Diethyl1,1-cyclopropyl dicarboxylate is selectively hydrolyzed to give amonocarboxylic acid. (ii) An amine group is introduced into themonocarboxylic acid according to the known Curtious Reaction (see: S.Linke, G. T. Tisue and W. Lowowski, J. Am. Chem. Soc. 1967, 89, 6308).(iii) The amine group is protected with a suitable protecting group [P²may be carbamate or various benzyl protecting groups, or alkyl group(methyl, ethyl, etc.)]. (iv) The opposite ester group is reduced into ahydroxy group, which is then protected (P¹ is defined as previouslydescribed). (v) The compound protected with protecting groups is reactedwith methyl iodide in the presence of sodium hydride to introduce methylgroup into the amine group. (vi) The amine-protecting group is removedand the resulting compound is reacted with dialkylbromomethylphosphonateto give the desired phosphonate compound. (vii) The alcohol-protectinggroup (P¹) is removed from the phosphonate compound thus obtained andthen a leaving group (L) is introduced to give the compound of formula(12).

The specific reaction conditions of the above processes can be referredto the following Preparations and Examples.

After the reaction is completed, the resulting product may be furtherseparated and purified by usual work-up processes, such as for example,chromatography, recrystallization, etc.

The compound of formula (1) of the present invention can be effectivelyused as an antiviral agent. Therefore, it is another object of thepresent invention to provide a composition for the treatment of viraldiseases, which comprises as an active ingredient the compound offormula (1), pharmaceutically acceptable salt, hydrate, solvate orisomer thereof together with the pharmaceutically acceptable carrier.

When the active compound according to the present invention is used forclinical purpose, it is preferably administered in an amount ranginggenerally from 0.1 to 10000 mg, preferably from 0.5 to 100 mg per kg ofbody weight a day. The total daily dosage may be administered in once orover several times. However, the specific administration dosage for thepatient can be varied with the specific compound used, body weight, sexor hygienic condition of the subject patient, diet, time or method ofadministration, excretion rate, mixing ratio of the agent, severity ofthe disease to be treated, etc.

The compound of the present invention may be administered in the form ofinjections or oral preparations.

Injections, for example, sterilized aqueous or oily suspension forinjection, can be prepared according to the known procedure usingsuitable dispersing agent, wetting agent, or suspending agent. Solventswhich can be used for preparing injections include water, Ringer's fluidand isotonic NaCl solution, and also sterilized fixing oil may beconveniently used as the solvent or suspending media. Anynon-stimulative fixing oil including mono-, di-glyceride may be used forthis purpose. Fatty acid such as oleic acid may also be used forinjections.

As the solid preparation for oral administration, capsules, tablets,pills, powders and granules, etc., preferably capsules and tablets canbe mentioned. It is also desirable for tablets and pills to beformulated into enteric-coated preparation. The solid preparations maybe prepared by mixing the active compound of formula (1) according tothe present invention with at least one carrier selected from a groupconsisting of inactive diluents such as sucrose, lactose, starch, etc.,lubricants such as magnesium stearate, disintegrating agent and bindingagent.

When the compound according to the present invention is clinicallyapplied for obtaining the desired antiviral effect, the active compoundof formula (1) can be administered in combination with one or moresubstances selected from the known anti-cancer or antiviral agents. Asthe anti-cancer or antiviral agents which can be administered togetherwith the compound of the present invention in such a manner,5-Fluorouracil, Cisplatin, Doxorubicin, Taxol, Gemcitabine, Lamivudine,etc. can be mentioned.

However, preparations comprising the compound of the present inventionare not restricted to those explained above, but may contain anysubstances useful for the treatment or prevention of cancers or viraldiseases.

The present invention will be more specifically explained in thefollowing Examples and Experiments. However, it should be understoodthat these Examples and Experiments are intended to illustrate thepresent invention but not in any manner to limit the scope of thepresent invention.

Preparation 1 Synthesis of1-({[t-butyl(diphenyl)silyl]oxy}methyl)cyclopropanol

According to the description in a reference (see: Syn. Lett. 07,1053-1054, 1999), the title compound was prepared as follows. 12 g (35mmole) of ethyl 2-{[t-butyl(diphenyl)silyl]oxy}acetate was dissolved in200 ml of tetrahydrofuran (THF) and 2.2 ml of titaniumtetraisopropoxidewas added thereto. To the mixture was slowly added 29.2 ml ofethylmagnesiumbromide (3.0M in THF), and the reaction solution wasstirred for 12 hours at room temperature. 20 ml of saturated ammoniumchloride was added to stop the reaction. About 150 ml of tetrahydrofuran(THF) used as a solvent was removed by distillation under reducedpressure, and the reaction mixture was extracted twice with 200 ml ofethyl acetate. The ethyl acetate extract was distilled under reducedpressure to give 11.4 g (Yield 100%) of the title compound as a whitesolid.

¹H NMR (CDCl₃) δ 0.44 (q, 2H), 0.78 (q, 2H), 1.09 (s, 9H), 3.67 (s, 2H),7.41 (m, 6H), 7.70 (m, 4H)

ESI: 344 (M+NH₄)⁺, C20H26O2Si

Preparation 2 Synthesis ofdiisopropyl{[1-({[t-butyl(diphenyl)silyl]oxy}methyl)cyclopropyl]oxy}methylphosphonate

The compound prepared in Preparation 1 (6.5 g) was dissolved in 10 ml ofdimethylformamide (DMF), 32 ml of lithium t-butoxide (1.0M in THF) wasadded thereto, and the resulting mixture was stirred for 10 minutes. Tothe mixture was added 7.0 g of diisopropyl bromomethylphosphonate, andthen the temperature was raised to 40° C. and the mixture was stirredfor 4 hours. Dimethylformamide (DMF) was removed by distillation underreduced pressure, 40 ml of saturated ammonium chloride was added to theresidue, which was then extracted with ethyl acetate. The ethyl acetateextract was distilled under reduced pressure and the residue waspurified by silica gel column chromatography (eluent: ethylacetate/n-hexane=1/1, v/v) to give 6.8 g (Yield 70%) of the titlecompound.

¹H NMR (CDCl₃) δ 0.53 (m, 2H), 0.88 (m, 2H), 1.07 (s, 9H), 1.29 (t,12H), 3.78 (s, 2H), 3.98 (d, 6H), 4.75 (m, 2H), 7.40 (m, 6H), 7.67 (m,4H)

Preparation 3 Synthesis ofdiisopropyl{1-[(hydroxymethyl)cyclopropyl]oxy}methylphosphonate

The compound prepared in Preparation 2 (8.3 g) was dissolved in 100 mlof methanol, 3.1 g of ammonium fluoride was added thereto, and theresulting mixture was heated under reflux for 2 hours. After thereaction was completed, methanol was removed by distillation underreduced pressure and the residue was purified by silica gel columnchromatography (eluent: dichloromethane/methanol=20/1, v/v) to give 3.6g (Yield 82%) of the title compound.

¹H NMR (CDCl₃) δ 0.60 (t, 2H), 0.87 (t, 2H), 1.28 (d, 12H), 2.5 (br s,1H), 3.65 (s, 2H), 3.83 (d, 2H), 4.82 (m, 2H)

ESI: 267 (M+1)⁺, C11H23O4P

Preparation 4 Synthesis of{1-[(diisopropoxyphosphoryl)methoxy]cyclopropyl}methylmethane-sulfonate

The compound prepared in Preparation 3 (1.5 g) was dissolved in 50 ml ofdichloromethane, 0.85 ml of triethylamine and 0.84 g ofmethanesulfonylchloride were added thereto, and the resulting mixturewas stirred for 30 minutes at room temperature. Saturated ammoniumchloride was added to stop the reaction. The product was extracted withdichloromethane and the dichloromethane extract was concentrated bydistillation under reduced pressure. The residue was purified by silicagel column chromatography (eluent: ethyl acetate/n-hexane=1/1, v/v) togive 1.63 g (Yield 81%) of the title compound.

¹H NMR (CDCl₃) δ 0.77 (m, 2H), 1.09 (m, 2H), 1.32 (m, 12H), 3.10 (s,3H), 3.82 (m, 2H), 4.33 (s, 2H), 4.71 (m, 2H)

Preparation 5 Synthesis ofdiisopropyl({1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate

The compound prepared in Preparation 4 (430 mg) was dissolved in 18 mlof dimethylformamide, 57.6 mg (60% purity) of sodium hydride and 162 mgof adenine were added thereto, and the resulting mixture was heatedunder reflux over 4 hours. Saturated ammonium chloride was added to stopthe reaction. The product was extracted with ethyl acetate, and theethyl acetate extract was distilled under reduced pressure. The residuewas purified by silica gel column chromatography (eluent:dichloromethane/methanol=20/1, v/v) to give 201 mg (Yield 44%) of thetitle compound.

¹H NMR (CDCl₃) δ 0.86 (t, 2H), 1.01 (t, 2H), 1.24 (d, 6H), 1.34 (d, 6H),3.86 (d, 2H), 4.34 (s, 2H), 4.71 (m, 2H), 5.97 (br s, 2H), 8.32 (s, 1H),8.58 (s, 1H)

ESI: 384 (M+1)⁺, C16H25N5O4P

Preparation 6 Synthesis ofdiisopropyl({1-[(2-amino-6-chloro-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate

The compound prepared in Preparation 4 (1.64 g) was dissolved in 70 mlof dimethylformamide, 219 mg (60% purity) of sodium hydride and 773 mgof 2-amino-6-chloro-9H-purine were added thereto, and the resultingmixture was stirred for 4 hours while heating at a temperature of up to80° C. Saturated ammonium chloride was added to stop the reaction. Theproduct was extracted with ethyl acetate, and the ethyl acetate extractwas distilled under reduced pressure. The residue was purified by silicagel column chromatography (eluent: dichloromethane/methanol=20/1, v/v)to give 765 mg (Yield 40%) of the title compound.

¹H NMR (CDCl₃) δ 0.80 (t, 2H), 1.02 (t, 2H), 1.27 (d, 6H), 1.28 (d, 6H),3.82 (d, 2H), 4.21 (s, 2H), 4.68 (m, 2H), 5.13 (br s, 2H), 8.15 (s, 1H)

ESI: 418 (M+1)⁺, C16H25ClN5O4P

Preparation 7 Synthesis ofdiisopropyl[(1{[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]methyl}cyclopropyl)oxy]methylphosphonate

The compound prepared in Preparation 4 (118 mg) and thymine were reactedaccording to the same procedure as Preparation 6 to give 26 mg (Yield21%) of the title compound.

¹H NMR (CDCl₃) δ 0.82 (t, 2H), 0.95 (t, 2H), 1.31 (m, 12H), 1.92 (s,3H), 3.74 (d, 2H), 3.89 (s, 2H), 4.71 (m, 2H), 7.62 (s, 1H), 9.15 (s,1H)

ESI: 375 (M+1)⁺, C16H27N2O6P

Preparation 8 Synthesis of1-({[t-butyl(diphenyl)silyl]oxy}methyl)-2-methylcyclopropanol

According to the description in a reference (see: Syn. Lett. 07,1053-1054, 1999), the title compound was prepared as follows. 50 g (146mmole) of ethyl 2-{[t-butyl(diphenyl)silyl]oxy}acetate was dissolved in700 ml of tetrahydrofuran (THF) and 30.0 ml of titaniumtetraisopropoxidewas added thereto. To the mixture was slowly added 290 ml ofpropylmagnesiumchloride (2.0M in THF) at −10° C., and the reactionsolution was stirred for 12 hours at room temperature. 200 ml ofsaturated ammonium chloride was added to stop the reaction. Thetetrahydrofuran (THF) used as a solvent was removed by distillationunder reduced pressure, and the reaction mixture was extracted twicewith 2000 ml of n-hexane. The n-hexane extract was distilled underreduced pressure and purified by silica gel column to give 42 g of thetitle compound.

¹H NMR (CDCl₃) δ 0.06 (t, 1H), 0.88 (dd, 2H), 0.97 (d, 3H), 1.09 (s, 9H)1.1 (m, 1H), 2.78 (s, 1H), 3.70 (d, 1H), 3.86 (d, 1H), 7.41 (m, 6H),7.70 (m, 4H)

ESI: 363 (M+Na)⁺, C21H28O2Si

Preparation 9 Synthesis ofdiisopropyl{[1-({[t-butyl(diphenyl)silyl]oxy}methyl)-2-methylcyclopropyl]oxy}methylphosphonate

The compound prepared in Preparation 8 (4.2 g) was reacted according tothe same procedure as Preparation 2 to give 3.3 g of the title compound.

¹H NMR (CDCl₃) δ 0.04 (t, 1H), 0.96 (dd, 1H), 0.97 (d, 3H), 1.05 (m,1H), 1.06 (s, 9H), 1.23 (t, 12H), 3.72 (d, 1H), 3.95 (d, 2H), 3.98 (d,1H), 4.75 (m, 2H), 7.40 (m, 6H), 7.68 (m, 4H)

Preparation 10 Synthesis ofdiisopropyl{1-[(hydroxymethyl)-2-methylcyclopropyl]oxy}methylphosphonate

The compound prepared in Preparation 9 (3.3 g) was reacted according tothe same procedure as Preparation 3 to give 1.7 g of the title compound.

¹H NMR (CDCl₃) δ 0.03 (t, 1H), 0.95 (dd, 1H), 0.96 (m, 1H), 1.11 (d,3H), 1.35 (d, 12H), 2.17 (br s, 1H), 3.80 (d, 2H), 3.96 (d, 1H), 4.80(m, 2H)

ESI: 303 (M+Na)⁺, C12H225O4

Preparation 11 Synthesis ofdiisopropyl({1-[(6-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonate

The compound prepared in Preparation 10 (1.5 g) was dissolved in 50 mlof dichloromethane, 0.85 ml of triethylamine and 0.84 g ofmethanesulfonylchloride were added thereto, and the resulting mixturewas stirred for 30 minutes at room temperature. Saturated ammoniumchloride was added to stop the reaction. The product was extracted withdichloromethane and the dichloromethane extract was concentrated bydistillation under reduced pressure. The residue was used in the nextreaction without any purification.

¹H NMR (CDCl₃) δ 0.42 (m, 1H), 1.12 (d, 3H), 1.25 (m, 1H), 1.32 (m,12H), 1.33 (m, 1H), 3.10 (s, 3H), 3.76 (m, 2H), 4.31 (d, 1H), 4.71 (d,1H), 4.76 (m, 2H)

The methanesulfonate thus obtained (430 mg) was dissolved in 18 ml ofdimethylformamide, and 57.6 mg (60% purity) of sodium hydride and 162 mgof adenine were added thereto. The reaction mixture was refluxed underheating over 4 hours. Saturated ammonium chloride was added to stop thereaction. The product was extracted with ethyl acetate and the ethylacetate extract was concentrated by distillation under reduced pressure.The residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=20/1, v/v) to give 201 mg (Yield 44%) of thetitle compound.

¹H NMR (CDCl₃) δ 0.53 (t, 1H), 1.13 (d, 3H), 1.15 (m, 1H), 1.30 (m,12H), 1.41 (m, 1H), 1.85 (brs, 2H), 3.81 (m, 2H), 4.43 (m, 2H), 4.70 (m,2H), 5.65 (br s, 2H), 8.26 (s, 1H), 8.34 (s, 1H)

ESI: 398 (M+1)⁺, C17H28N5O4P

Preparation 12 Synthesis ofdiisopropyl({1-[(2-amino-6-chloro-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonate

The compound prepared in Preparation 10 was reacted according to thesame procedure as Preparation 11 except that 6-chloroguanine(2-amino-6-chloro-9H-purine) was used instead of adenine to give thetitle compound.

¹H NMR (CDCl₃) δ 0.47 (t, J=6.4 Hz, 1H), 1.12 (m, 4H), 1.24 (dd, J=2.8Hz, 6.4 Hz, 6H), 1.28 (t, J=6.0 Hz, 6H), 1.38 (m, 1H), 3.80 (m, 2H),4.28 (m, 2H), 4.68 (m, 2H), 5.13 (brs, 2H), 8.15 (s, 1H)

ESI: 432 (M+1)⁺, C17H27ClN5O4P

Preparation 13 Synthesis ofdiisopropyl[(1{[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]methyl}-2-methylcyclopropyl)oxy]methylphosphonate

The compound prepared in Preparation 10 was reacted according to thesame procedure as Preparation 11 except that thymine was used instead ofadenine to give the title compound.

¹H NMR (CDCl₃) δ 0.48 (t, 1H), 1.10 (m, 4H), 1.24 (dd, 6H), 1.28 (t,J=6H), 1.38 (m, 1H), 1.92 (s, 3H), 3.80 (m, 2H), 4.28 (m, 2H), 4.68 (m,2H), 7.62 (s, 1H), 9.15 (s, 1H)

ESI: 389 (M+1)⁺′ C17H29N2O6P

Preparation 14 Synthesis of 1-(ethoxycarbonyl)cyclopropanecarboxylicacid

Diethyl 1,1-cyclopropane dicarboxylate (20 g) was hydrolyzed in 1N NaOH(107 ml) and ethanol (220 ml) for 16 hours, and the ethanol was removedby distillation under reduced pressure. The remaining starting materialwas removed by using ethyl acetate and the aqueous layer was acidifiedby 1N HCl. The reaction mixture was extracted with ethyl acetate anddistilled under reduced pressure. The residue was purified by silica gelcolumn to give the title compound in a yield of 94%.

¹H NMR (CDCl₃) δ 1.06 (t, 3H), 1.53 (m, 2H), 1.62 (m, 2H), 4.21 (q, 2H)

ESI: 159 (M+1)⁺ C7H10O4

Preparation 15 Synthesis of ethyl1-{[(benzyloxy)carbonyl]amino}cyclopropanecarboxylate

The carboxylic acid prepared in Preparation 14 (16 g) was dissolved indichloromethane, 10.8 ml of oxalyl chloride was added dropwise, and 2drops of dimethylformamide was added. The reaction mixture was stirredat room temperature for 3 hours and distilled under reduced pressure togive ethoxycarbonyl 1,1-cyclopropane carbonylchloride. This compound,not purified, was dissolved in 30 ml of dimethylformamide and theresulting solution was cooled with water-ice. 36 g of NaN₃ was added andthe reaction was carried out at room temperature for 3 hours. Thereaction solution was extracted with 100 ml of water and 200 ml ofdiethylether, and the diethylether extract was concentrated to givecrude compound which was purified by silica gel column to give an azidecompound.

¹H NMR (CDCl₃) δ 1.28 (t, 3H), 1.54 (m, 4H), 4.19 (q, 2H)

To the azide compound thus obtained (13 g) was added dropwise 11 ml ofbenzyl alcohol and the reaction mixture was heated to 100° C., by whichthe reactants were vigorously reacted with each other with thegeneration of gas. The reaction mixture was heated at 100° C. forfurther 1 hour, cooled to room temperature, and distilled under reducedpressure to remove benzyl alcohol. The residue was purified by silicagel column to give the title compound.

¹H NMR (CDCl₃) δ 1.19 (m, 5H), 1.54 (m, 2H), 4.11 (m, 2H), 5.15 (br.s,2H), 7.32 (m, 5H)

Preparation 16 Synthesis of benzyl1-{[t-butyl(diphenylsilyl)oxy]methylcyclopropyl}(methyl)carbamate

The carboxylate prepared in Preparation 15 (13.2 g) was dissolved indiethylether, to which 1.3 g of LiBH₄ dissolved in diethylether wasslowly added dropwise. The reaction misture was stirred at roomtemperature for 16 hours, and 50 ml of methanol and 5 ml of 1N HCl wereadded dropwise thereto. The reaction mixture was stirred for 2 hours,the precipitate was removed by suction filtration, and the solvent inthe filtrate was removed by distillation under reduced pressure. Theresidue was purified by silica gel column to give benzyl1-(hydroxymethyl)cyclopropylcarbamate.

This compound (9.3 g) was dissolved in dichloromethane, and 4.2 g ofimidazole and 13.5 ml of t-butyldiphenylsilylchloride were added inorder. The reaction mixture was stirred at room temperature for 4 hoursand the solvent was removed by distillation under reduced pressure. Theresidue was purified by silica gel column to give benzyl1-({[t-butyl(diphenyl)silyl]oxy}methyl)cyclopropylcarbamate.

¹H NMR (CDCl₃) δ 0.71-1.19 (m, 4H), 1.04 (s, 9H), 3.68 (br.s, 2H), 5.04(s, 2H), 7.25-7.45 (m, 11H), 7.62 (d, 4H)

The carbamate thus obtained (5.5 g) was dissolved in THF, 3.5 ml ofmethane iodide (MeI) was added dropwise and then 1 g of NaH was added.The reaction mixture was stirred at room temperature for 4 hours andthen extracted with 100 ml of diethylether and 100 ml of water. Thediethylether extract was concentrated by distillation under reducedpressure and the residue was purified by silica gel column to give thetitle compound.

¹H NMR (CDCl₃) δ 0.78-0.84 (m, 4H), 1.03 (s, 9H), 3.03 (s, 3H),3.55-3.80 (m, 2H), 5.10 (s, 2H), 7.24-7.45 (m, 11H), 7.61 (m, 4H)

Preparation 17 Synthesis ofdiisopropyl[1-({[t-butyl(diphenyl)silyl]oxy}methyl)cyclopropyl)(methyl)amino]methylphosphonate

The carbamate prepared in Preparation 16 (1.0 g) was dissolved inethanol, 100 mg of 10% Pd/C was added, and the reaction mixture wassubjected to a hydrogenation under hydrogen atmosphere. After thereaction was completed, the solvent was removed by distillation underreduced pressure. The residue was purified by silica gel column to give1-({[t-butyl(diphenyl)silyl]oxy}methyl)-N-methylcyclopropaneamine.

¹H NMR (CDCl₃) δ 0.36 (m, 2H), 0.65 (m, 2H), 1.05 (s, 9H), 2.36 (s, 3H),3.57 (s, 2H), 7.37-7.45 (m, 11H), 7.66 (d, 4H)

The methylcyclopropaneamine thus obtained (1.0 g) was dissolved indichloromethane, to which 1.03 ml of diisopropylethylamine and 1.3 ml of(diisopropyl phosphoryl)methyl trifluoromethansulfonate were addeddropwise. The reaction mixture was reacted under stirring at roomtemperature for 4 hours, and then extracted with 100 ml of diethyletherand 100 ml of water. The solvent in the diethylether extract was removedby distillation under reduced pressure and the residue was purified bysilica gel column to give the title compound.

¹H NMR (CDCl₃) δ 0.42 (m, 2H), 0.69 (m, 2H), 1.04 (s, 9H), 1.25 (d, 6H),1.30 (d, 6H), 2.62 (s, 3H), 3.25 (d, 2H), 3.64 (s, 2H), 4.68 (m, 2H),7.39 (m, 6H), 7.65 (d, 4H)

Preparation 18 Synthesis ofdiisopropyl(1-{[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}(methyl)amino)methylphosphonate

The compound prepared in Preparation 17 (0.32 g) was dissolved inmethanol and 1.5 g of ammonium fluoride was added dropwise. The reactionmixture was reacted under stirring at 60° C. for 24 hours and then thesolvent was removed by distillation under reduced pressure. The residuewas purified by silica gel column to givemethylaminediisopropylmethylphosphone 1,1-cyclopropane ethyl alcohol.

¹H NMR (CDCl₃) δ 0.56 (m, 2H), 0.73 (m, 2H), 1.31 (m, 12H), 2.56 (s,3H), 3.11 (d, 2H), 3.55 (s, 2H), 4.70 (m, 2H)

The compound thus obtained was consecutively reacted according to thesame procedure as Preparations 4 and 5 to give the title compound.

¹H NMR (CDCl₃) δ 0.78 (m, 2H), 0.86 (m, 2H), 1.25 (m, 12H), 2.35 (s,3H), 4.10 (s, 2H), 4.68 (m, 2H), 5.13 (m, 2H), 8.32 (s, 1H), 8.58 (s,1H)

ESI: 397 (M+1)⁺, C17H29N6O3P

Preparation 19 Synthesis ofdiisopropyl(1-{[(2-amino-6-chloro-9H-purin-9-yl)methyl]cyclopropyl}(methyl)amino)methylphosphonate

The compound prepared in Preparation 17 (0.32 g) was dissolved inmethanol and 1.5 g of ammonium fluoride was added dropwise. The reactionmixture was reacted under stirring at 60° C. for 24 hours and then thesolvent was removed by distillation under reduced pressure. The residuewas purified by silica gel column to givemethylaminediisopropylmethylphosphone 1,1-cyclopropane ethyl alcohol.

¹H NMR (CDCl₃) δ 0.56 (m, 2H), 0.73 (m, 2H), 1.31 (m, 12H), 2.56 (s,3H), 3.11 (d, 2H), 3.55 (s, 2H), 4.70 (m, 2H)

The compound thus obtained was consecutively reacted according to thesame procedure as Preparations 4 and 6 to give the title compound.

¹H NMR (400 MHz, CD₃OD): δ 0.79 (m, 2H), 0.89 (m, 2H), 1.26 (m, 12H),2.38 (s, 3H), 2.76 (d, 2H, J=7 Hz), 4.11 (s, 2H), 4.65 (m, 2H), 5.13 (m,2H), 8.02 (s, 1H)

ESI: 431 (M+1)⁺, C17H28ClN6O3P

Preparation 20 Synthesis ofdiisopropyl[(1-{[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]methyl}cyclopropyl)(methyl)amino]methylphosphonate

The compound prepared in Preparation 17 (0.32 g) was dissolved inmethanol and 1.5 g of ammonium fluoride was added dropwise. The reactionmixture was reacted under stirring at 60° C. for 24 hours and then thesolvent was removed by distillation under reduced pressure. The residuewas purified by silica gel column to givemethylaminediisopropylmethylphosphone 1,1-cyclopropane ethyl alcohol.

¹H NMR (CDCl₃) δ 0.56 (m, 2H), 0.73 (m, 2H), 1.31 (m, 12H), 2.56 (s,3H), 3.11 (d, 2H), 3.55 (s, 2H), 4.70 (m, 2H)

The compound thus obtained was consecutively reacted according to thesame procedure as Preparations 4 and 7 to give the title compound.

¹H NMR (CDCl₃) δ 0.79 (m, 2H), 0.90 (m, 2H), 1.31 (m, 12H), 1.92 (s,3H), 2.38 (s, 3H), 3.75 (d, 2H), 4.10 (s, 2H), 4.65 (m, 2H), 7.62 (s,1H), 9.15 (s, 1H)

Preparation 21 Synthesis of 1,1-cyclopropanedicarboxylic acid

In 50% NaOH 187 ml was dissolved 15 g of diethylmalonate at roomtemperature. Benzyltriethylammoniumchloride (21.3 g) was added and theresulting mixture was stirred for 10 minutes. 1,2-Dibromoethane (12.3 g)was added to the reaction solution and the resulting mixture was stirredfor more than 18 hours at room temperature. The reaction mixture wasneutralized by adding dropwise conc. sulfuric acid and then extractedwith ethyl acetate. The extract was distilled under reduced pressure togive 6.2 g of the title compound as a white solid.

¹H NMR (CDCl₃) δ 1.88 (s, 4H)

Preparation 22 Synthesis of[1-({[t-butyl(diphenyl)silyl]oxy}methyl)cyclopropyl]methanol

Lithium aluminum hydride (LAH) 15.3 g was dissolved in 39 g oftetrahydrofuran, and 11.7 g of the carboxylic acid prepared inPreparation 21 was slowly added dropwise at 0° C. The reaction solutionwas refluxed for 17 hours. The reaction was stopped by adding 10% HCl atroom temperature and the mixture was extracted with ethyl acetate. Theextract was distilled under reduced pressure and the residue waspurified by silica gel column to give 8.2 g of diol compound.

¹H NMR (CDCl₃) δ 0.56 (s, 4H), 2.22 (s, 2H), 3.63 (s, 4H)

The compound thus obtained (400 mg) was dissolved in 12 ml of THF, 184mg of NaH and 1.16 g of t-butyldiphenylsilylchloride (TBDPSCl) wereadded, and the resulting mixture was refluxed for 6 hours. The reactionwas stopped by adding 10 ml of water and the mixture was extracted withethyl acetate. The extract was distilled under reduced pressure and theresidue was purified by silica gel column to give 1.1 g of the titlecompound.

¹H NMR (CDCl₃) δ 0.33 (t, 2H), 0.48 (t, 2H), 1.23 (s, 9H), 3.59 (d, 4H),7.42 (m, 6H), 7.68 (m, 4H)

Preparation 23 Synthesis ofdiethyl(E)-2-[1-({[t-butyl(diphenyl)silyl]oxy}methyl)cyclopropyl]ethenylphosphonate

The compound prepared in Preparation 22 (2 g) was dissolved in 50 ml ofdichloromethane, and 1.03 g of N-methylmorpholine N-oxide and 103 mg oftetrapropylammoniumperruthenate (TPAP) were added thereto at roomtemperature. The reaction mixture was stirred for about 1 hour at roomtemperature and the reaction was stopped by adding 20 ml of water. Thereaction solution was extracted with dichloromethane and the extract wasconcentrated under reduced pressure to give 2.0 g of aldehyde compound.

¹H NMR (CDCl₃) δ 1.03 (s, 9H), 1.04 (t, 2H), 1.05 (t, 2H), 3.94 (s, 2H),7.37 (m, 6H), 7.64 (m, 4H), 9.10 (s, 1H)

Tetraethylmethylene diphosphonate (1.7 g) was dissolved in 60 ml oftetrahydrofuran (THF). At −78° C., 264 mg of NaH was added, theresulting mixture was stirred for 20 minutes, and then 1.9 g of thealdehyde compound as obtained above was added. The reaction solution wasstirred at room temperature for 1 hour, and the reaction was stopped byadding 20 ml of water. The reaction solution was extracted with ethylacetate and the extract was concentrated under reduced pressure. Theresidue was purified by silica gel column to give 2.32 g of the titlecompound.

¹H NMR (CDCl₃) δ 0.76 (t, 2H), 0.81 (t, 2H), 1.04 (s, 9H), 1.31 (t, 6H),3.71 (s, 2H), 4.05 (m, 4H), 5.70 (m, 1H), 6.42 (m, 1H), 7.43 (m, 6H),7.64 (d, 4H)

ESI: 501 (M+1)⁺′ C28H41O4PSi

Preparation 24 Synthesis of diethyl2-[1-(hydroxymethyl)cyclopropyl]ethenylphosphonate

The compound prepared in Preparation 23 was reacted according to thesame procedure as Preparation 3 to give the title compound.

¹H NMR (CDCl₃) δ 0.76 (t, 2H), 0.81 (t, 2H), 1.04 (s, 9H), 1.31 (t, 6H),3.71 (s, 2H), 4.05 (m, 4H), 5.70 (m, 1H), 6.42 (m, 1H), 7.43 (m, 6H),7.64 (d, 4H)

ESI: 501 (M+1)⁺′ C28H41O4PSi

Preparation 25 Synthesis of diethyl2-{1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}ethenylphosphonate

The compound prepared in Preparation 24 was reacted according to thesame procedure as Preparations 4 and 5 to give the title compound.

¹H NMR (CDCl₃) δ 1.07 (t, 2H), 1.19 (t, 2H), 1.22 (t, 6H), 3.93 (s, 4H),4.33 (s, 2H), 5.55 (s, 2H), 5.63 (m, 1H), 6.49 (m, 1H), 7.88 (s, 1H),8.37 (s, 1H)

ESI: 352 (M+1)⁺′ C15H22N5O3P

Preparation 26 Synthesis of diethyl2-{1-[(2-amino-6-chloro-9H-purin-9-yl)methyl]cyclopropyl}ethenylphosphonate

The compound prepared in Preparation 24 was reacted according to thesame procedure as Preparations 4 and 6 to give the title compound.

¹H NMR (CDCl₃) δ 1.06 (t, 2H), 1.15 (t, 2H), 1.23 (t, 6H), 3.93 (s, 4H),4.18 (s, 2H), 5.12 (s, 2H), 5.59 (m, 1H), 6.58 (m, 1H), 7.81 (s, 1H)

ESI: 386 (M+1)⁺′ C15H21ClN5O3P

Preparation 27 Synthesis of diethyl2-(1-{[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]methyl}cyclopropyl)ethenylphosphonate

The compound prepared in Preparation 24 was reacted according to thesame procedure as Preparations 4 and 7 to give the title compound.

¹H NMR (CDCl₃) δ 0.93 (t, 2H), 1.01 (t, 2H), 1.24 (t, 6H), 1.92 (s, 3H),3.91 (s, 2H), 3.96 (m, 4H), 5.49 (m, 1H), 5.87 (m, 1H), 7.62 (s, 1H).9.15 (s, 1H)

ESI: 343 (M+1)⁺′ C15H23N2O5P

Preparation 28 Synthesis of1-({[t-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethylcyclopropanol

According to the description in a reference (see: Syn. Lett. 07,1053-1054, 1999), the title compound was prepared as follows. 10 g (29mmole) of ethyl 2-{[t-butyl(diphenyl)silyl]oxy}acetate was dissolved in100 ml of tetrahydrofuran (THF) and 6.0 ml of titaniumtetraisopropoxidewas added thereto. To the mixture was slowly added 37 ml ofisobutylmagnesiumbromide (2.0M in THF) at −10° C., and the reactionsolution was stirred for 12 hours at room temperature. 50 ml ofsaturated ammonium chloride was added to stop the reaction. Thetetrahydrofuran (THF) used as a solvent was removed by distillationunder reduced pressure, and the reaction mixture was extracted twicewith 500 ml of n-hexane. The n-hexane extract was distilled underreduced pressure and purified by silica gel column to give 5.0 g of thetitle compound.

¹H NMR (CDCl₃) δ 0.25 (d, 1H), 0.51 (d, 2H), 0.99 (s, 3H), 1.07 (s, 9H),1.22 (s, 3H), 3.71 (d, 1H), 3.91 (d, 1H), 7.41 (m, 6H), 7.70 (m, 4H)

ESI: 355 (M+1)⁺, C22H30O2Si

Preparation 29 Synthesis ofdiisopropyl{[1-({[t-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethylcyclopropyl]oxy}methylphosphonate

The compound prepared in Preparation 28 was reacted according to thesame procedure as Preparation 2 to give the title compound.

¹H NMR (CDCl₃) δ 0.29 (d, 1H), 0.60 (d, 1H), 1.06 (s, 3H), 1.09 (s, 9H),1.27 (s, 3H), 1.30 (m, 12H), 3.75 (m, 2H), 3.92 (m, 2H), 4.72 (m, 2H),7.41 (m, 6H), 7.67 (m, 4H)

ESI: 519 (M+1)⁺, C28H43O5PSi

Preparation 30 Synthesis ofdiisopropyl{1-[(hydroxymethyl)-2,2-dimethylcyclopropyl]oxy}methylphosphonate

The compound prepared in Preparation 29 was reacted according to thesame procedure as Preparation 3 to give the title compound.

¹H NMR (CDCl₃) δ 0.39 (d, 1H), 0.59 (d, 1H), 1.13 (s, 3H), 1.21 (s, 3H),1.33 (d, 12H), 3.76 (m, 2H), 3.86 (m, 2H), 4.76 (m, 2H)

ESI: 295 (M+1)⁺, C13H27O4P

Preparation 31 Synthesis ofdiisopropyl({1-[(6-amino-9H-purin-9-yl)methyl]-2,2-dimethylcyclopropyl}oxy)methylphosphonate

The compound prepared in Preparation 30 was reacted according to thesame procedure as Preparation 11 to give the title compound.

¹H NMR (500 MHz, CDCl₃): δ 0.62 (d, J=5.9 Hz, 1H), 0.81 (d, J=5.9 Hz,1H), 1.10 (s, 3H), 1.23 (m, 15H), 3.72 (dd, J=15.1, 11.0 Hz, 1H), 3.85(dd, J=15.1, 5.5 Hz, 1H), 4.28 (d, J=15.1 Hz, 1H), 4.58 (d, J=15.1 Hz,1H), 4.68 (m, 2H), 5.79 (bs, 2H), 8.19 (s, 1H), 8.32 (s, 1H)

ESI: 412 (M+1)⁺, C18H30N5O4P

Preparation 32 Synthesis ofdiisopropyl({1-[(2-amino-6-iodo-9H-purin-9-yl)methyl]-2,2-dimethylcyclopropyl}oxy)methylphosphonate

The compound prepared in Preparation 30 was reacted according to thesame procedure as Preparation 12 except that 6-iodoguanine was usedinstead of 6-chloroguanine to give the title compound.

¹H NMR (500 MHz, CDCl₃): δ 0.58 (d, J=6.4 Hz, 1H), 0.80 (d, J=6.4 Hz,1H), 1.10 (s, 3H), 1.24 (m, 8H), 3.72 (dd, J=13.0, 11.0 Hz, 1H), 3.88(dd, J=13.0, 9.3 Hz, 1H) 4.08 (d, J=15.1 Hz, 1H), 4.47 (d, J=15.1 Hz,1H), 4.67 (m, 2H), 5.05 (bs, 1H), 8.10 (s, 1H)

ESI: 538 (M+1)⁺, C18H29IN5O4P

Preparation 33 Synthesis ofdiisopropyl[(1{[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]methyl}-2,2-dimethylcyclopropyl)oxy]methylphosphonate

The compound prepared in Preparation 30 was reacted according to thesame procedure as Preparation 13 to give the title compound.

¹H NMR (CDCl₃) δ 0.58 (d, 1H), 0.80 (d, 1H), 1.10 (s, 3H), 1.24 (dd,6H), 1.28 (t, 6H), 1.58 (s, 3H), 1.92 (s, 3H), 3.72 (dd, 1H), 3.88 (dd,1H), 4.08 (d, 1H), 4.47 (d, 1H), 4.67 (m, 2H), 7.62 (s, 1H), 9.15 (s,1H)

ESI: 403 (M+1)⁺′ C18H31N2O6P

Preparation 34 Synthesis of1-[1-({[t-butyl(diphenyl)silyl]oxy}methyl)cyclopropyl]-1-methyl alcohol

6 g of the compound prepared in Preparation 22 was dissolved in 150 mlof dichloromethane. 3.0 g of N-oxide and 103 mg oftetrapropylammoniumperruthenate (TPAP) were added thereto at roomtemperature. The reaction mixture was stirred for about 1 hour at roomtemperature and quenched by adding 20 ml of water. The reaction mixturewas extracted with dichloromethane and the extract was concentratedunder reduced pressure to give 6.0 g of aldehyde compound which went tonext reaction without further purification.

5.23 g of the aldehyde was dissolved in 350 ml of THF. The solution wascooled to −78° C. and 10.3 ml of methylmagnesiumbromide (3.0M solution)was slowly added to the solution and then, stirred for 1 hour at roomtemperature. The reaction mixture was quenched by 0.5 ml of water and0.5 ml of methanol and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent: ethylacetate/n-hexane=1/8, v/v) to 3.57 g of title compound.

¹H NMR (CDCl₃) δ 0.22 (m, 1H), 0.39 (m, 2H), 0.61 (m, 1H), 1.06 (s, 9H),1.24 (d, 3H), 3.3 (d, 1H), 3.47 (s, 2H), 3.9 (d, 1H), 7.43 (m, 6H), 7.64(m, 6H)

Preparation 35 Synthesis of diethyl(E)-2-1-[1-({[t-butyl(diphenyl)silyl]oxy}methyl)cyclopropyl]-1-propenylphosphonate

4 g of the compound prepared in preparation 34 was dissolved in 10 ml ofdichloromethane. 2.1 g of n-morpholine N-oxide and 209 mg oftetrapropylammoniumperruthenate (TPAP) were added thereto at roomtemperature. The reaction mixture was stirred for about 1 hour at roomtemperature and quenched by adding 20 ml of water. The reaction mixturewas extracted with dichloromethane and the extract was concentratedunder reduced pressure to give 4.0 g of compound which went to nextreaction without further purification.

Tetraethylmethylene diphosphonate (2.7 g) was dissolved in 30 ml oftetrahydrofuran (THF) at −78 and 4 ml of n-butyllithium was added. Theresulting mixture was stirred for 20 minutes, and then 1.0 g of theketone compound as obtained above was added. The reaction mixture wasstirred at room temperature for 1 hour and was stopped by adding 20 mlof water. The reaction mixture was extracted with ethyl acetate andconcentrated under reduced pressure. The residue was purified by silicagel column to give 654 mg of the title compound.

¹H NMR (CDCl₃) δ 0.58 (m, 1H), 0.69 (m, 2H), 1.02 (s, 9H), 1.20 (t, 6H),2.09 (d, 3H), 3.59 (s, 2H), 4.05 (m, 4H), 5.61 (d, 1H), 7.38 (m, 6H),7.63 (d, 4H)

Example 1 Synthesis of({1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid(Compound 1)

The compound prepared in Preparation 5 (159 mg) was dissolved in 15 mlof dichloromethane, 1.27 g of trimethylsilylbromide was added thereto,and the resulting mixture was heated under reflux for 18 hours. Afterthe completion of reaction, the reaction mixture was extracted withwater, and the water extract was distilled under reduced pressure. Theresidue was purified by high performance liquid chromatography (HPLC) togive 0.89 g (Yield 90%) of the title compound as a white powder.

¹H NMR (MeOH-d4) δ 1.02 (d, 4H), 3.95 (d, 2H), 4.55 (s, 2H), 8.40 (s,1H), 8.55 (s, 1H)

ESI: 300 (M+1)⁺, C10H14N5O4P

Example 2 Synthesis of3-[({1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-ylpivalate (Compound 2)

The title compound was prepared according to the method known in areference (see: J. Med. Chem., 37(12), 1857 (1994)) and U.S. Pat. No.5,663,159 (1998).

The compound prepared in Example 1 (1.00 g) was dissolved in 150 ml ofdry dimethylformamide, and 2.08 g (7.32 mmol) ofN,N′-dicyclohexyl-4-morpholine-carboxamidine and 2.75 g (18.3 mmol) ofchloromethyl pivalate were added thereto. When the reaction mixturebecame homogeneous after about 1 hour, it was stirred for 5 days at roomtemperature. The reaction solution was filtered, the filtrate wasconcentrated under reduced pressure, and the residue was fractionatedwith 50 ml of water and 50 ml of toluene to separate the organic layer.The aqueous layer was extracted twice with 50 ml of toluene. Thecombined organic layers were concentrated under reduced pressure. Theresidue was purified by column chromatography (eluent:methanol/dichloromethane=1/20, v/v) to give 0.59 g (Yield 32%) of thetitle compound as a white solid.

¹H NMR (500 MHz, CDCl₃) δ 0.91 (m, 2H), 1.12 (m, 2H), 1.20 (m, 18H),1.90 (br s, 2H), 3.90 (d, 2H), 4.32 (s, 2H), 5.65 (m, 4H), 8.14 (s, 1H),8.31 (s, 1H)

ESI: 528 (M+1)⁺, C22H34N5O8P

Example 3 Synthesis of({1-[(2-amino-6-chloro-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid (Compound 3)

The compound prepared in Preparation 6 (73 mg) was reacted according tothe same procedure as Example 1 to give 46 mg (Yield 80%) of the titlecompound.

¹H NMR (MeOH-d4) δ 1.00 (s, 2H), 1.07 (s, 2H), 3.94 (d, 2H), 4.52 (s,2H), 9.50 (s, 1H)

ESI: 334 (M+1)⁺, C10H13ClN5O4P

Example 4 Synthesis of({1-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonicacid (Compound 5)

The compound prepared in Example 3 (41 mg) was dissolved in 5 ml of 2Nhydrochloric acid and heated under reflux for 6 hours. Water was removedby distillation under reduced pressure to give 37 mg (Yield 95%) of thetitle compound as a white solid.

¹H NMR (MeOH-d4) δ 0.98 (m, 2H), 1.06 (m, 2H), 3.92 (d, 2H), 4.45 (s,2H), 9.20 (s, 1H)

ESI: 316 (M+1)⁺, C10H14N5O5P

Example 5 Synthesis of({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid(Compound 9)

The compound prepared in Preparation 6 (150 mg) was dissolved in 15 mlof tetrahydrofuran, 15 mg of 5% palladium/carbon was added thereto, andthe compound was reduced under 1 atm of hydrogen atmosphere for 18hours. After completion of reaction, palladium/carbon was removed bysuction filtration and the filtrate was distilled under reducedpressure. The residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/1, v/v) to give 130 mg ofdiisopropyl compound (ESI: 384(M+1)⁺, C16H26N5O4P). This compound wastreated with trimethylsilylbromide according to the same procedure asExample 1 to give 91 mg (Yield 90%) of the title compound.

¹H NMR (MeOH-d4) δ 0.94 (m, 2H), 1.03 (m, 2H), 3.93 (d, 2H), 4.40 (s,2H), 8.66 (s, 1H), 8.74 (s, 1H)

ESI: 300 (M+1)⁺, C10H14N5O4P

Example 6 Synthesis of3-[({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-ylpivalate (Compound 10)

The compound prepared in Example 5 was reacted according to the sameprocedure as Example 2 to give the title compound.

¹H NMR (CDCl₃-d4) δ 0.90 (m, 2H), 1.05 (m, 2H), 1.20 (m, 18H), 3.96 (d,2H), 4.22 (s, 2H), 5.65 (m, 4H), 8.03 (s, 1H), 8.69 (s, 1H)

ESI: 528 (M+1)⁺, C22H34N5O8P

Example 7 Synthesis of({1-[(2-amino-6-cyclopropylamino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonicacid (Compound 11)

The compound prepared in Preparation 6 (200 mg) was dissolved in 20 mlof ethanol, 53 ml of triethylamine and 82 mg of cyclopropylamine wereadded thereto, and the resulting mixture was heated under reflux for 18hours. Water was added to stop the reaction, and the product wasextracted with ethyl acetate. The ethyl acetate extract was concentratedby distillation under reduced pressure and the residue was purified bysilica gel column chromatography (eluent: dichloromethane/methanol=20/1,v/v) to give 178 mg (Yield 85%) of the diisopropyl compound.

¹H NMR (CDCl₃) δ 0.59 (t, 2H), 0.83 (m, 4H), 1.00 (t, 2H), 1.24 (d, 6H),1.29 (d, 6H), 3.0 (brs, 1H), 3.80 (d, 2H), 4.15 (s, 2H), 4.70 (m, 2H),4.71 (brs, 2H), 5.71 (s, 1H), 7.68 (s, 1H)

The compound thus obtained was treated with trimethylsilylbromideaccording to the same procedure as Example 1 to give 128 mg (Yield 90%)of the title compound.

¹H NMR (MeOH-d4) δ 0.86 (m, 2H), 0.94 (m, 2H), 1.02 (m, 2H), 1.07 (m,2H), 2.90 (br s, 1H), 3.93 (d, 2H), 4.39 (s, 2H), 8.43 (br s, 1H)

ESI: 355 (M+1)⁺, C13H19N6O4P

Example 8 Synthesis of({1-[(2-amino-6-ethylamino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonicacid (Compound 13)

The compound prepared in Preparation 6 (115 mg) was dissolved in 2 ml ofethanol, 31 ml of triethylamine and 0.07 ml of ethylamine were addedthereto, and the resulting mixture was heated under reflux for 18 hours.Water was added to stop the reaction, and the product was extracted withethyl acetate. The ethyl acetate extract was concentrated bydistillation under reduced pressure and the residue was purified bysilica gel column chromatography (eluent: dichloromethane/methanol=20/1,v/v) to give 104 mg (Yield 89%) of the diisopropyl compound.

¹H NMR (CDCl₃) δ 0.82 (m, 2H), 1.00 (m, 2H), 1.24 (d, 6H), 1.27 (t, 3H),1.29 (d, 6H), 3.60 (brs, 2H), 3.81 (d, 2H), 4.15 (s, 2H), 4.65 (m, 4H),5.50 (br s, 1H), 7.78 (s, 1H)

The compound thus obtained was reacted according to the same procedureas Example 1 to give 75 mg (Yield 90%) of the title compound.

¹H NMR (MeOH-d4) δ 0.89 (m, 2H), 1.04 (m, 2H), 1.31 (t, 3H), 3.59 (br s,2H), 3.92 (d, 2H), 4.35 (s, 2H), 9.95 (br s, 1H)

ESI: 343 (M+1)⁺, C13H19N6O4P

Example 9 Synthesis of[(1-{[2-amino-6-(dimethylamino)-9H-purin-9-yl]methyl}cyclopropyl)oxy]methylphosphonicacid (Compound 15)

The compound prepared in Preparation 6 (115 mg) was dissolved in 20 mlof ethanol, 38.6 ml of triethylamine and 1.74 ml of N,N-dimethylaminewere added thereto, and the resulting mixture was heated under refluxfor 18 hours. Water was added to stop the reaction, and the product wasextracted with ethyl acetate. The ethyl acetate extract was concentratedby distillation under reduced pressure and the residue was purified bysilica gel column chromatography (eluent: dichloromethane/methanol=20/1,v/v) to give 119 mg (Yield 81%) of the diisopropyl compound.

¹H NMR (CDCl₃) δ 0.75 (t, 2H), 0.93 (t, 2H), 1.16 (d, 6H), 1.22 (d, 6H),3.3 (brs, 6H), 3.74 (d, 2H), 4.09 (s, 2H), 4.60 (m, 2H), 4.69 (brs, 2H),7.68 (s, 1H)

The compound thus obtained was reacted according to the same procedureas Example 1 to give 86 mg (Yield 90%) of the title compound.

¹H NMR (MeOH-d4) δ 0.89 (m, 2H), 1.05 (m, 2H), 3.30 (br s, 6H), 3.90 (d,2H), 4.37 (s, 2H), 7.92 (br s, 1H)

ESI: 343 (M+1)⁺, C12H19N6O4P

Example 10 Synthesis of[(1-{[2-amino-6-(isopropylamino)-9H-purin-9-yl]methyl}cyclopropyl)oxy]methylphosphonicacid (Compound 17)

The compound prepared in Preparation 6 (133 mg) was dissolved in 20 mlof ethanol, 0.049 ml of triethylamine and 0.082 ml of isopropylaminewere added thereto, and the resulting mixture was heated under refluxfor 18 hours. Water was added to stop the reaction, and the product wasextracted with ethyl acetate. The ethyl acetate extract was concentratedby distillation under reduced pressure and the residue was purified bysilica gel column chromatography (eluent: dichloromethane/methanol=20/1,v/v) to give 95 mg (Yield 68%) of the diisopropyl compound.

¹H NMR (CDCl₃) δ 0.83 (m, 2H), 0.98 (m, 2H), 1.28 (m, 18H), 3.79 (d,2H), 4.15 (s, 2H), 4.60 (br s, 1H), 4.68 (s, 2H), 4.70 (m, 2H), 5.40 (brs, 1H), 7.77 (s, 1H)

The compound thus obtained was reacted according to the same procedureas Example 1 to give 72 mg (Yield 91%) of the title compound.

¹H NMR (MeOH-d4) δ 0.89 (m, 2H), 1.05 (m, 2H), 1.34 (d, 6H), 3.30 (br s,1H), 3.90 (d, 2H), 4.36 (s, 2H), 8.01 (br s, 1H)

ESI: 357 (M+1)⁺, C12H19N6O4P

Example 11 Synthesis of({1-[(2,6-diamino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonicacid (Compound 19)

The compound prepared in Preparation 4 (246 mg) and 2,6-diaminopurinewere reacted according to the same procedure as Preparation 5 to give78.5 mg (Yield 29%) of the diisopropyl compound.

¹H NMR (CDCl₃) δ 0.85 (t, 2H), 1.00 (t, 2H), 1.25 (d, 6H), 1.29 (d, 6H),1.83 (brs, 2H), 3.82 (d, 2H), 4.15 (s, 2H), 4.68 (m, 2H), 5.39 (d, 2H),7.85 (s, 1H)

ESI: 399 (M+1)⁺, C16H27N6O4P

The compound thus obtained was reacted according to the same procedureas Example 1 to give 72 mg (Yield 91%) of the title compound.

¹H NMR (DMSO-d6+CF₃COOH) δ 0.70 (m, 2H), 0.82 (m, 2H), 3.58 (d, 2H),4.21 (s, 2H), 8.16 (br s, 1H)

ESI: 315 (M+1)⁺, C10H15N6O4P

Example 12 Synthesis of({1-[(2-amino-6-ethoxy-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonicacid (Compound 23)

6-Chloroguanine derivative prepared in Preparation 6 (100 mg) wasdissolved in 10 ml of ethanol, 32 ml of triethylamine and 53 mg ofsodium methoxide were added, and the resulting mixture was refluxed for4 hours. The reaction was stopped by adding 10 ml of water. The reactionsolution was extracted with dichloromethane and distilled under reducedpressure. The residue was purified by silica gel column to give acompound wherein 6-position of guanine was substituted by ethoxy group.

¹H NMR (CDCl₃) δ 0.83 (t, 2H), 1.00 (t, 2H), 1.24-1.28 (m, 12H), 1.45(t, 3H), 3.82 (d, 2H), 4.21 (s, 2H), 4.53 (m, 2H), 4.67 (m, 1H), 5.76(s, 2H), 7.90 (s, 1H)

The compound thus obtained was reacted according to the same procedureas Example 1 to give the title compound.

¹H NMR (MeOH-d4) δ 0.99 (t, 2H), 1.06 (t, 2H), 1.48 (t, 3H), 3.91 (d,2H), 4.51 (s, 2H), 4.65 (m, 2H), 9.18 (s, 1H)

ESI: 344 (M+1)⁺, C12H18N5O5P

Example 13 Synthesis of({1-[(2-amino-6-methyl-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonicacid (Compound 25)

10 ml flask was dried under vacuum and 53 mg (0.238 mmol) of zincbromide was introduced bit by bit under nitrogen atmosphere. 2 ml of drytetrahydrofuran was added dropwise thereto, the temperature was loweredto −78° C., 0.08 ml (20.238 mmol) of methylmagnesium bromide was added,and the resulting mixture was stirred for 1 hour. After the reactionmixture was warmed to room temperature, about 10 mol % ofpalladiumtetrakistriphenylphosphine was added bit by bit. 50 mg (0.119mmol) of the compound prepared in Preparation 6 in 1 ml oftetrahydrofuran was added to the above reaction solution dropwise. Theresulting mixture was heated for 1 hour. The solvent was removed bydistillation under reduced pressure, the residue was participated withwater and ethyl acetate, and the organic layer was concentrated bydistillation under reduced pressure. The residue was purified by silicagel column chromatography (eluent: methylene chloride/methanol=90/10,v/v) to give 20 mg (Yield 42%) of the diisopropyl compound.

¹H NMR (MeOH-d4) δ 0.95 (m, 2H), 0.98 (m, 2H), 1.17 (d, 6H), 1.23 (d,6H), 2.59 (s, 3H), 4.02 (s, 1H), 4.10 (s, 1H), 4.32 (s, 2H), 4.59 (m,2H), 8.12 (s, 1H)

ESI: 398 (M+1)⁺, C17H28N5O4P

The compound thus obtained was reacted according to the same procedureas Example 1 to give 8.0 mg (Yield 50%) of the title compound.

¹H NMR (D₂O) δ 0.87 (m, 2H), 1.02 (m, 2H), 3.79 (s, 1H), 3.81 (s, 1H),4.53 (s, 2H), 8.25 (s, 1H)

ESI: 314 (M+1)⁺, C11H16N5O4P

Example 14 Synthesis of[(1{[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]methyl}cyclopropyl)oxy]methylphosphonicacid (Compound 31)

The compound prepared in Preparation 7 (19 mg) was reacted according tothe same procedure as Example 1 to give 14 mg (Yield 95%) of the titlecompound.

ESI: 291 (M+1)⁺, C10H11N2O6P

¹H NMR (MeOH-d4) δ 0.82 (t, 2H), 0.97 (t, 2H), 1.87 (s, 3H), 3.83 (d,2H), 3.97 (s, 2H), 7.55 (s, 1H)

Example 15 Synthesis of[(1-{[2-amino-6-(4-morpholinyl)-9H-purin-9-yl]methyl}cyclopropyl)oxy]methylphosphonicacid (Compound 37)

The compound prepared in Preparation 6 (134 mg) was dissolved in 20 mlof ethanol, 0.049 ml of triethylamine and 0.085 ml of morpholine wereadded thereto, and the resulting mixture was heated under reflux for 18hours. Water was added to stop the reaction, and the product wasextracted with ethyl acetate. The ethyl acetate extract was concentratedby distillation under reduced pressure and the residue was purified bysilica gel column chromatography (eluent: dichloromethane/methanol=20/1,v/v) to give 66 mg (Yield 44%) of the diisopropyl compound.

¹H NMR (CDCl₃) δ 0.83 (m, 2H), 0.99 (m, 2H), 1.24 (d, 6H), 1.30 (d, 6H),3.79 (m, 6H), 4.18 (s, 2H), 4.21 (br s, 4H), 4.67 (m, 2H), 4.80 (br s,2H), 7.78 (s, 1H)

ESI: 469 (M+1)⁺, C20H33N6O5P

The compound thus obtained was treated with trimethylsilylbromideaccording to the same procedure as Example 1 to give 49 mg (Yield 91%)of the title compound.

¹H NMR (MeOH-d4) δ 0.89 (m, 2H), 1.07 (m, 2H), 3.81 (m, 4H), 3.92 (d,2H), 4.40 (br s, 6H), 7.87 (s, 1H)

ESI: 384 (M+1)⁺, C14H21N6O5P

Example 16 Synthesis of[(1-{[2-amino-6-(1-piperidinyl)-9H-purin-9-yl]methyl}cyclopropyl)oxy]methylphosphonicacid (Compound 39)

The compound prepared in Preparation 6 (154 mg) was dissolved in 20 mlof ethanol, 0.049 ml of triethylamine and 0.11 ml of piperidine wereadded thereto, and the resulting mixture was heated under reflux for 18hours. Water was added to stop the reaction, and the product wasextracted with ethyl acetate. The ethyl acetate extract was concentratedby distillation under reduced pressure and the residue was purified bysilica gel column chromatography (eluent: dichloromethane/methanol=20/1,v/v) to give 123 mg (Yield 72%) of the diisopropyl compound.

¹H NMR (CDCl₃) δ 0.80 (m, 2H), 0.99 (m, 2H), 1.22 (d, 6H), 1.26 (d, 6H),1.63 (m, 4H), 1.67 (m, 2H), 3.78 (d, 2H), 4.14 (s, 6H), 4.54 (br s, 2H),4.65 (m, 2H), 7.72 (s, 1H) ESI: 467 (M+1)⁺, C21H35N6O4P

The compound thus obtained was reacted according to the same procedureas Example 1 to give 87 mg (Yield 91%) of the title compound.

¹H NMR (MeOH-d4) δ 0.89 (m, 2H), 1.06 (m, 2H), 1.73 (m, 4H), 1.79 (m,2H), 3.90 (d, 2H), 4.37 (s, 2H), 4.43 (br s, 4H), 7.89 (s, 1H)

ESI: 383 (M+1)⁺, C15H23N6O4P

Example 17 Synthesis of[(1-{[2-amino-6-(4-methyl-1-piperazinyl)-9H-purin-9-yl]methyl}cyclopropyl)oxy]methylphosphonicacid (Compound 41)

The compound prepared in Preparation 6 (128 mg) was dissolved in 20 mlof ethanol, 0.10 ml of 4-methyl-1-piperazine was added thereto, and theresulting mixture was heated under reflux for 18 hours. Water was addedto stop the reaction, and the product was extracted with ethyl acetate.The ethyl acetate extract was concentrated by distillation under reducedpressure and the residue was purified by silica gel columnchromatography (eluent: dichloromethane/methanol=20/1, v/v) to give 123mg (Yield 83%) of the diisopropyl compound.

¹H NMR (CDCl₃) δ 0.80 (m, 2H), 0.98 (m, 2H), 1.21 (d, 6H), 1.27 (d, 6H),2.30 (s, 3H), 2.48 (m, 4H), 3.78 (d, 2H), 4.13 (s, 2H), 4.22 (br s, 4H),4.57 (s, 2H), 4.66 (m, 2H), 7.73 (s, 1H)

ESI: 482 (M+1)⁺, C21H36N7O4P

The compound thus obtained was reacted according to the same procedureas Example 1 to give 87 mg (Yield 85%) of the title compound.

¹H NMR (MeOH-d4) δ 0.89 (m, 2H), 1.07 (m, 2H), 3.00 (s, 3H), 3.72 (m,4H), 3.91 (d, 2H), 4.45 (s, 2H), 4.89 (m, 2H), 5.70 (br, 2H), 7.91 (s,1H)

ESI: 398 (M+1)⁺, C15H24N7O4P

Example 18 Synthesis of[(1-{[2-amino-6-(1-pyrrolidinyl)-9H-purin-9-yl]methyl}cyclopropyl)oxy]methylphosphonic acid (Compound 43)

The compound prepared in Preparation 6 (122 mg) was dissolved in 20 mlof ethanol, 0.07 ml of pyrrolidine was added thereto, and the resultingmixture was heated under reflux for 18 hours. Water was added to stopthe reaction, and the product was extracted with ethyl acetate. Theethyl acetate extract was concentrated by distillation under reducedpressure and the residue was purified by silica gel columnchromatography (eluent: dichloromethane/methanol=20/1, v/v) to give 110mg (Yield 83%) of the diisopropyl compound.

¹H NMR (CDCl₃) δ 0.78 (m, 2H), 0.96 (m, 2H), 1.20 (d, 6H), 1.26 (d, 6H),2.00 (br s, 4H), 3.60 (br, 3H), 3.78 (d, 2H), 4.09 (br, 2H), 4.12 (s,2H), 4.63 (m, 2H), 7.69 (s, 1H)

ESI: 453 (M+1)⁺, C20H33N6O4P

The compound thus obtained was reacted according to the same procedureas Example 1 to give 76 mg (Yield 85%) of the title compound.

¹H NMR (MeOH-d4) δ 0.94 (m, 2H), 1.03 (m, 2H), 2.15 (m, 4H), 3.76 (m,2H), 3.91 (d, 2H), 4.18 (m, 2H), 4.40 (s, 2H), 5.70 (br, 2H), 8.42 (s,1H)

ESI: 369 (M+1)⁺, C14H21N6O4P

Example 19 Synthesis of3-[({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-9-methyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphadec-1-yl3-methylbutanoate (Compound 74)

The compound prepared in Example 5 (100 mg) was dissolved indimethylformamide (2 ml) and then reacted with chloromethyl3-methylbutyrate in the presence of triethylamine (3 equivalents) atroom temperature for 24 hours. The resulting product was purified bysilica gel column to give the title compound in a yield of 41%.

¹H NMR (CDCl₃) δ 0.89 (t, 2H), 0.94 (d, 12H), 1.04 (t, 2H), 2.10 (m,2H), 2.22 (d, 4H), 3.97 (d, 2H), 4.23 (s, 2H), 5.21 (s, 2H), 5.65 (m,4H), 8.00 (s, 1H), 8.69 (s, 1H)

ESI: 527 (M+1)⁺, C23H35N4O8P

Example 20 Synthesis of3-[({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-3,7-dioxo-2,4,6-trioxa-38⁵-phosphadec-1-ylbutyrate (Compound 75)

The compound prepared in Example 5 was reacted with chloromethylbutyrate according to the same procedure as Example 19 at roomtemperature for 24 hours. The resulting product was purified by silicagel column to give the title compound in a yield of 24%.

¹H NMR (CDCl₃) δ 0.88 (t, 2H), 0.92 (d, 6H), 1.60 (m, 4H), 2.32 (t, 4H),3.96 (d, 2H), 4.22 (s, 2H), 5.00 (s, 2H), 5.62 (m, 4H), 8.00 (s, 1H),8.68 (s, 1H)

ESI: 499 (M+1)⁺, C21H31N4O8P

Example 21 Synthesis of3-[({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8-methyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-yl2-methylpropanoate (Compound 78)

The compound prepared in Example 5 was reacted with chloromethylisobutyrate according to the same procedure as Example 19 at roomtemperature for 24 hours. The resulting product was purified by silicagel column to give the title compound in a yield of 21%.

¹H NMR (CDCl₃) δ 0.84 (t, 2H), 0.97 (t, 2H), 1.11 (d, 12H), 2.52 (m,2H), 3.91 (d, 2H), 4.16 (s, 2H), 5.21 (s, 2H), 5.58 (m, 4H), 7.96 (s,1H), 8.61 (s, 1H)

ESI: 499 (M+1)⁺, C21H31N4O8P

Example 22 Synthesis of3-[({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-3,7-dioxo-7-(1-pyrrolidinyl)-2,4,6-trioxa-38⁵-phosphahept-1-yl-pyrrolidinecarboxylate(Compound 80)

The compound prepared in Example 5 was reacted with chloromethyl1-pyrrolidinecarboxylate according to the same procedure as Example 19at room temperature for 24 hours. The resulting product was purified bysilica gel column to give the title compound in a yield of 35%.

¹H NMR (CDCl₃) δ 0.82 (t, 2H), 0.87 (m, 8H), 0.98 (t, 2H), 1.57 (d, 4H),2.26 (t, 4H), 3.91 (d, 2H), 4.16 (s, 2H), 5.12 (s, 2H), 5.57 (m, 4H),7.98 (s, 1H), 8.62 (s, 1H)

ESI: 553 (M+1)⁺, C23H33N6O8P

Example 23 Synthesis of3-[({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-3,7-dioxo-7-(1-piperidinyl)-2,4,6-trioxa-38⁵-phosphahept-1-yl1-piperidinecarboxylate (Compound 81);

The compound prepared in Example 5 was reacted with chloromethyl1-piperidinecarboxylate according to the same procedure as Example 19 atroom temperature for 24 hours. The resulting product was purified bysilica gel column to give the title compound in a yield of 39%.

¹H NMR (CDCl₃) δ 0.86 (t, 2H), 1.02 (t, 2H), 1.47-1.58 (brm, 12H), 3.40(brm, 8H), 3.99 (d, 2H), 4.22 (s, 2H), 5.00 (s, 2H), 5.69 (m, 4H), 8.00(s, 1H), 8.67 (s, 1H)

ESI: 581 (M+1)⁺, C25H37N6O8P

Example 24 Synthesis of3-[({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-7-(4-morpholinyl)-3,7-dioxo-2,4,6-trioxa-38⁵-phosphahept-1-yl4-morpholinecarboxylate (Compound 82)

The compound prepared in Example 5 was reacted with chloromethyl4-morpholinecarboxylate according to the same procedure as Example 19 atroom temperature for 24 hours. The resulting product was purified bysilica gel column to give the title compound in a yield of 40%.

¹H NMR (CDCl₃) δ 0.89 (t, 2H), 1.03 (t, 2H), 3.47 (brm, 8H), 3.65 (brm,8H), 4.00 (d, 2H), 4.24 (s, 2H), 5.04 (s, 2H), 5.70 (m, 4H), 8.07 (s,1H), 8.69 (s, 1H)

ESI: 586 (M+1)⁺, C23H33N6O10P

Example 25 Synthesis of{[1-({2-amino-6-[(4-methylphenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonicacid (Compound 66)

6-Chloroguanine derivative prepared in Preparation 6 (4.86 g) wasdissolved in 85 ml of methanol and 1.4 g of triethylamine and 2.9 g of4-methylthiocresol were added. The reaction mixture was reacted underreflux condition for 24 hours. The reaction was stopped by adding 20 mlof water, and the methanol was removed by distillation under reducedpressure. The reaction mixture was extracted with dichloromethane andpurified by silica gel column to give a compound wherein 6-position ofguanine was substituted by 4-methylphenylthio group.

¹H NMR (CDCl₃) δ 0.84 (t, 2H), 1.02 (t, 2H), 1.25-1.31 (m, 12H), 2.40(s, 3H), 4.20 (d, 2H), 4.69 (m, 2H), 4.74 (s, 2H), 7.22 (d, 2H), 7.50(d, 2H), 8.00 (s, 1H)

The compound thus obtained was reacted according to the same procedureas Example 1 and then recrystallized from a mixture ofmethanol-diethylether (1/20, v/v) to give the title compound.

¹H NMR (MeOH-d4) δ 0.98 (t, 2H), 1.06 (t, 2H), 2.42 (s, 3H), 3.92 (d,2H), 4.48 (s, 2H), 7.35 (d, 2H), 7.55 (d, 2H), 9.05 (s, 1H)

ESI: 421 (M+1)⁺, C18H21N4O4PS

Example 26 Synthesis of3-({[1-({2-amino-6-[(4-methylphenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-38⁵-phosphanon-1-ylpivalate (Compound 68)

The methylphosphonic acid prepared in Example 25 was reacted accordingto the same procedure as Example 2 to give the title compound.

¹H NMR (CDCl₃) δ 0.82 (t, 2H), 0.98 (t, 2H), 1.18 (s, 18H), 2.36 (s,3H), 3.93 (d, 2H), 4.15 (s, 2H), 4.93 (s, 2H), 5.60 (m, 4H), 7.18 (d,2H), 7.48 (d, 2H), 7.88 (s, 1H)

ESI: 649 (M+1)⁺, C30H41N4O8PS

Example 27 Synthesis of{[1-({2-amino-6-[(4-methoxyphenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonicacid (Compound 96)

6-Chloroguanine derivative prepared in Preparation 6 (4.86 g) wasdissolved in 85 ml of methanol and 1.4 g of triethylamine and 2.9 g of4-methoxythiocresol were added. The reaction mixture was reacted underreflux condition for 24 hours. The reaction was stopped by adding 20 mlof water, and the methanol was removed by distillation under reducedpressure. The reaction mixture was extracted with dichloromethane andpurified by silica gel column to give a compound wherein 6-position ofguanine was substituted by 4-methoxyphenylthio group.

The compound thus obtained was reacted according to the same procedureas Example 1 and then recrystallized from a mixture ofmethanol-diethylether (1/20, v/v) to give the title compound.

¹H NMR (MeOH-d4) δ 0.77 (m, 2H), 1.05 (m, 2H), 3.87 (s, 3H), 3.92 (d,2H), 4.45 (s, 2H), 7.10 (d, 2H), 7.59 (d, 2H), 8.09 (s, 1H)

ESI: 438 (M+1)⁺, C17H20N5O5PS

Example 28 Synthesis of{[1-({2-amino-6-[(4-nitrophenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonicacid (Compound 95)

The compound prepared in Preparation 6 was reacted according to the sameprocedure as Example 27 except that 4-nitrothiocresol was used insteadof 4-methoxythiocresol to give the title compound.

¹H NMR (MeOH-d4) δ 0.86 (m, 2H), 0.95 (m, 2H), 3.82 (d, 2H), 4.35 (s,2H), 7.81 (d, 2H), 8.22 (d, 2H), 8.72 (s, 1H)

ESI: 453 (M+1)⁺, C16H17N6O6PS

Example 29 Synthesis of({1-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonicacid (Compound 97)

The 6-chloroguanine derivative prepared in Preparation 12 wasconsecutively reacted according to the same procedure as Examples 3 and4 to give the title compound.

¹H NMR (MeOH-d4) δ 0.73 (t, 1H), 1.15 (m, 1H), 1.21 (d, 3H), 1.38 (t,1H), 1.48 (m, 1H), 3.85 (t, 1H), 3.96 (t, 1H), 4.42 (d, 1H), 4.69 (d,1H), 9.12 (s, 1H)

Example 30 Synthesis of{[1-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-9H-purin-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonicacid (Compound 99)

The 6-chloroguanine derivative prepared in Preparation 12 was reactedaccording to the same procedure as Example 27 to give the titlecompound.

¹H NMR (MeOH-d4) δ 0.67 (t, 1H), 1.13 (m, 2H), 1.20 (d, 3H), 1.45 (m,1H), 3.85 (m, 1H), 3.86 (s, 3H), 3.94 (m, 1H), 4.42 (d, 1H), 4.68 (d,1H), 7.09 (d, 2H), 7.59 (d, 2H), 9.00 (s, 1H)

ESI: 452 (M+1)⁺, C18H22N5O5PS

Example 31 Synthesis of{[1-({2-amino-[6-(4-methylphenyl)sulfanyl]-9H-purin-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonicacid (Compound 101)

The 6-chloroguanine derivative prepared in Preparation 12 was reactedaccording to the same procedure as Example 25 to give the titlecompound.

¹H NMR (MeOH-d4) δ 0.68 (t, 1H), 1.15 (m, 2H), 1.20 (d, 3H), 1.45 (m,1H), 2.42 (s, 3H), 3.84 (m, 1H), 3.96 (m, 1H), 4.43 (d, 1H), 4.68 (d,1H), 7.36 (d, 2H), 7.55 (d, 2H), 9.05 (s, 1H)

ESI: 436 (M+1)⁺, C18H22N5O4PS

Example 32 Synthesis of{[1-({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purin-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonicacid (Compound 100)

The 6-chloroguanine derivative prepared in Preparation 12 was reactedaccording to the same procedure as Example 28 to give the titlecompound.

¹H NMR (MeOH-d4) δ 0.49 (t, 1H), 0.93 (m, 1H), 1.00 (d, 3H), 1.25 (m,1H), 3.64 (m, 1H), 3.76 (m, 1H), 4.28 (d, 1H), 4.53 (d, 1H), 7.72 (d,2H), 8.14 (d, 2H), 9.10 (s, 1H)

ESI: 467 (M+1)⁺, C17H19N6O6PS

Example 33 Synthesis of({1-[(6-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonicacid (Compound 103)

The adenine derivative prepared in Preparation 11 was reacted accordingto the same procedure as Example 1 to give the title compound.

¹H NMR (MeOH-d4) δ 0.64 (t, 1H), 1.09 (m, 1H), 1.20 (d, 3H), 1.43 (m,1H), 3.83 (m, 1H), 3.95 (m, 1H), 4.49 (d, 1H), 4.75 (d, 1H), 5.49 (s,2H), 8.39 (s, 1H), 8.55 (s, 1H)

ESI: 314 (M+1)⁺, C11H16N5O4P

Example 34 Synthesis ofbis{[(t-butoxycarbonyl)oxy]methyl}({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate(Compound 69)

The compound prepared in Example 5 (187 mg) was mixed with 6 ml ofN-methyl-2-pyrrolidone, and 300 mg of triethylamine and 150 mg ofchloromethyl t-butylcarbonate were added. The reaction solution wasstirred at room temperature for 4 hours. The reaction was stopped byadding 10 ml of water, and the reaction mixture was extracted with ethylacetate. The extract was distilled under reduced pressure and purifiedby silica gel column to give the title compound.

¹H NMR (CDCl₃) δ 0.86 (m, 2H), 1.06 (m, 2H), 1.47 (s, 18H), 4.01 (d,4H), 4.22 (s, 2H), 5.00 (brs, 2H), 5.61 (m, 4H), 7.99 (s, 1H), 8.69 (s,1H)

ESI: 344 (M+1)⁺, C22H34N5O10P

Example 35 Synthesis ofbis{[(isopropoxycarbonyl)oxy]methyl}({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate(Compound 70)

The compound prepared in Example 5 (100 mg) was mixed with 5 ml ofN-methyl-2-pyrrolidone, and 110 mg of triethylamine and 150 mg ofchloromethyl isopropylcarbonate were added. The reaction solution wasstirred at 50 for 4 hours. The reaction was stopped by adding 10 ml ofwater, and the reaction mixture was extracted with ethyl acetate. Theextract was distilled under reduced pressure and purified by silica gelcolumn to give the title compound.

¹H NMR (CDCl₃) δ 0.88 (s, 2H), 1.06 (s, 2H), 1.29 (d, 2H), 1.31 (d, 2H),4.01 (d, 4H), 4.21 (s, 2H), 4.92 (m, 2H), 5.01 (brs, 2H), 5.64 (m, 4H),7.99 (s, 1H), 8.69 (s, 1H)

ESI: 532 (M+1)⁺, C20H30N5O10P

Example 36 Synthesis of({1-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]-2,2-dimethylcyclopropyl}oxy)methylphosphonic acid (Compound 146)

The compound prepared in Preparation 32 was consecutively reactedaccording to the same procedure as Examples 1 and 4 to give the titlecompound.

¹H NMR (MeOH-d4) δ 0.78 (d, 1H), 0.82 (d, 1H), 1.21 (s, 3H), 1.27 (s,3H), 3.90 (d, 1H), 3.91 (d, 1H), 4.58 (s, 2H), 9.12 (s, 1H)

ESI: 344 (M+1)⁺, C12H18N5O5P

Example 37 Synthesis of({1-[(2-amino-9H-purin-9-yl)methyl]-2,2-dimethylcyclopropyl}oxy)methylphosphonicacid (Compound 147)

The compound prepared in Preparation 32 was reacted according to thesame procedure as Example 5 to give a compound wherein 6-position ofguanine was reduced by hydrogen.

¹H NMR (CDCl₃) δ 0.60 (d, 1H), 0.82 (d, 1H), 1.21 (s, 3H), 1.22 (s, 3H),1.22 (m, 15H), 3.73 (m, 1H), 3.87 (m, 1H), 4.13 (d, 1H), 4.49 (d, 1H),4.67 (m, 2H), 4.98 (brs, 2H), 8.09 (s, 1H), 9.67 (s, 1H)

The compound thus obtained was reacted according to the same procedureas Example 1 to give the title compound.

¹H NMR (MeOH-d4) δ 0.74 (d, 1H), 0.81 (d, 1H), 1.21 (s, 3H), 1.26 (s,3H), 3.91 (d, 2H), 4.49 (d, 1H), 4.57 (d, 1H), 8.63 (s, 1H), 8.74 (s,1H)

ESI: 328 (M+1)⁺, C12H18N5O4P

Example 38 Synthesis of({1-[(6-amino-9H-purin-9-yl)methyl]-2,2-dimethylcyclopropyl}oxy)methylphosphonicacid (Compound 148)

The compound prepared in Preparation 31 was reacted according to thesame procedure as Example 1 to give the title compound.

¹H NMR (MeOH-d4) δ 0.77 (d, 1H), 0.79 (d, 1H), 1.25 (s, 3H), 1.28 (s,3H), 3.90 (d, 2H), 4.61 (d, 1H), 4.70 (d, 1H), 8.38 (s, 1H), 8.51 (s,1H)

ESI: 328 (M+1)⁺, C12H18N5O4P

Example 39 Synthesis of(E)-2-{1-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl}ethenylphosphonicacid (Compound 130)

The compound prepared in Preparation 26 was reacted according to thesame procedure as Example 1 to give phosphonic acid derivative.

¹H NMR (MeOH-d4) δ 1.07 (t, 2H), 1.33 (t, 1H), 4.41 (s, 2H), 5.76 (dd,1H), 6.45 (dd, 1H), 9.18 (s, 1H)

The compound thus obtained was reacted according to the same procedureas Example 4 to give the title compound.

¹H NMR (MeOH-d4) δ 1.08 (t, 2H), 1.34 (t, 1H), 4.38 (s, 2H), 5.78 (dd,1H), 6.46 (dd, 1H), 9.11 (s, 1H)

ESI: 312 (M+1)⁺, C11H14N5O4P

Example 40 Synthesis of2-{1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}ethyl phosphonic acid(Compound 139)

The compound prepared in Preparation 26 was reacted according to thesame procedure as Example 5 to give the title compound.

¹H NMR (MeOH-d4) δ 0.58 (t, 2H), 0.85 (t, 2H), 1.42 (m, 2H), 1.95 (m,2H), 4.11 (s, 2H), 5.78 (dd, 1H), 8.55 (s, 1H), 8.75 (s, 1H)

ESI: 298 (M+1)⁺, C11H16N5O3P

Example 41 Synthesis of(E)-2-{1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}ethenyl phosphonicacid (Compound 132)

The compound prepared in Preparation 25 was reacted according to thesame procedure as Example 1 to give the title compound.

¹H NMR (MeOH-d4) δ 0.94 (t, 2H), 1.20 (t, 2H), 4.36 (s, 2H), 5.63 (dd,1H), 6.37 (dd, 1H), 8.30 (s, 1H), 8.31 (s, 1H)

ESI: 296 (M+1)⁺, C11H14N5O3P

Example 42 Synthesis of2-{1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}ethyl phosphonic acid(Compound 140)

The compound prepared in Preparation 25 was reacted according to thesame procedure as Example 5 to give the title compound.

¹H NMR (MeOH-d4) δ 0.58 (t, 2H), 0.87 (t, 2H), 1.37 (m, 2H), 1.97 (m,2H), 4.24 (s, 2H), 8.31 (s, 1H), 8.42 (s, 1H)

ESI: 298 (M+1)⁺, C11H16N5O3P

Example 43 Synthesis of2-{1-[(2-amino-6-hydroxy-9H-purin-9-yl)methyl]cyclopropyl}ethylphosphonicacid (Compound 138)

The compound prepared in Preparation 26 was reacted according to thesame procedure as Example 12 to give a compound wherein 6-position ofguanine was substituted by ethoxy group.

¹H NMR (CDCl₃) δ 1.00 (t, 2H), 1.10 (t, 2H), 1.16-1.21 (m, 9H), 3.90 (m,4H), 4.01 (m, 2H), 4.13 (s, 2H), 4.92 (s, 2H), 5.58 (dd, 1H), 6.49 (dd,1H), 7.62 (s, 1H)

The compound thus obtained (80 mg) was dissolved in methanol and reactedunder hydrogen atrmosphere in the presence of 20 mg of 10% Pd/C to givea compound wherein double bond was reduced.

¹H NMR (CDCl₃) δ 0.49 (t, 2H), 0.66 (t, 2H), 1.21 (t, 6H), 1.42 (m, 2H),2.01 (m, 2H), 3.99 (m, 6H), 4.96 (s, 2H), 7.59 (s, 1H)

The compound thus obtained was reacted according to the same procedureas Example 1 to give the title compound.

¹H NMR (MeOH-d4) δ 0.60 (t, 2H), 0.87 (t, 2H), 1.47 (m, 2H), 1.97 (m,2H), 4.16 (s, 2H), 9.12 (s, 1H)

ESI: 314 (M+1)⁺, C11H16N5O4P

Example 44 Synthesis of2-{1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}propyl phosphonic acid(Compound 144)

The compound prepared in Preparation 35 was consecutively reactedaccording to the same procedure as Preparations 24, 26 and Example 5 togive the title compound.

¹H NMR (MeOH-d4) δ 0.62-0.77 (m, 4H), 1.04 (d, 3H), 1.52 (m, 2H), 1.90(m, 1H), 4.24 (m, 2H), 8.58 (s, 1H), 8.74 (s, 1H)

ESI: 312 (M+1)⁺, C12H18N5O3P

Example 45 Synthesis of(E)-2-{1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}-1-propenylphosphonicacid (Compound 137)

The compound prepared in Preparation 35 was consecutively reactedaccording to the same procedure as Preparations 24, 25 and Example 1 togive the title compound.

¹H NMR (MeOH-d4) δ 0.86 (t, 2H), 1.10 (t, 2H), 2.19 (d, 3H), 4.38 (s,2H), 5.23 (d, 1H), 8.34 (s, 1H), 8.37 (s, 1H)

ESI: 310 (M+1)⁺, C12H16N5O3P

Example 46 Synthesis of2-{1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}propyl phosphonic acid(Compound 143)

The compound prepared in Preparation 35 was consecutively reactedaccording to the same procedure as Preparations 24, 25 and Example 5 togive the title compound.

¹H NMR (MeOH-d4) δ 0.65 (t, 2H), 0.78 (t, 2H), 0.95 (m, 1H), 1.00 (d,3H), 1.53 (s, 1H), 1.90 (m, 1H), 4.3 (q, 2H), 8.41 (s, 1H), 8.45 (s, 1H)

ESI: 312 (M+1)⁺, C12H18N5O3P

Example 47 Synthesis ofbis(2,2,2-trifluoroethyl)({1-[(6-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate(Compound 48)

To the methylphosphonic acid prepared in Example 1 (150 mg) was addeddropwise dichloromethane, 0.73 ml of N,N-diethyltrimethylsilylamine wasadded dropwise thereto, and the resulting mixture was stirred at roomtemperature for 2 hours. Oxalyl chloride (0.15 ml) and 2 drops ofdimethylformamide were added to the reaction vessel. The mixture wasstirred for further 2 hours and the solvent was removed by distillationunder reduced pressure. To the residue were added 10 ml of pyridine and2 ml of trifluoroethanol, which was then reacted under stirring for 16hours. The solvent was removed by distillation under reduced pressureand the residue was purified by silica gel column to give the titlecompound.

¹H NMR (CD₃OD) δ 1.02 (m, 4H), 4.30 (d, 2H), 4.53 (m, 6H), 8.40 (s, 1H),8.46 (s, 1H)

ESI: 464 [M+H]+: C14H16F6N5O4P

Example 48 Synthesis ofbis(2,2,2-trifluoroethyl)({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate(Compound 49)

The compound prepared in Example 5 was reacted according to the sameprocedure as Example 47 to give the title compound.

¹H NMR (CDCl₃) δ 0.88 (m, 2H), 1.04 (m, 2H), 4.07 (d, 2H), 4.22 (s, 2H),4.33 (m, 4H), 5.06 (br.s, 2H), 7.92 (s, 1H), 8.68 (s, 1H)

ESI: 464 [M+H]⁺, C14H16F6N5O4P

Example 49 Synthesis ofbis(2,2,2-trifluoroethyl)[1-({2-amino-[6-(4-methylphenyl)sulfanyl]-9H-purin-9-yl}methyl)cyclopropyl]oxy}methylphosphonate(Compound 62)

The compound prepared in Example 25 was reacted according to the sameprocedure as Example 47 to give the title compound.

¹H NMR (CDCl₃) δ 0.88 (m, 2H), 1.03 (m, 2H), 2.39 (s, 3H), 4.06 (d, 2H),4.19 (s, 2H), 4.33 (m, 4H), 4.76 (br.s, 2H), 7.22 (d, 2H), 7.50 (d, 2H),7.82 (s, 1H)

ESI: 586 [M+H]+, C21H22F6N5O4PS

Example 50 Synthesis ofbis(2,2,2-trifluoroethyl)[(1-{[2-amino-6-hydroxy-9H-purin-9-yl]methyl}cyclopropyl)oxy]methylphosphonate(Compound 45)

The compound prepared in Example 4 was reacted according to the sameprocedure as Example 47 to give the title compound.

¹H NMR (CDCl₃) δ 0.91 (m, 2H), 1.05 (m, 2H), 4.08 (d, 2H), 4.17 (s, 2H),4.35 (m, 4H), 4.70 (s, 2H), 7.69 (s, 1H)

MW=478 [M+H]+479 C14H16F6N5O5P

Example 51 Synthesis ofbis(2,2,2-trifluoroethyl)(1-{[2-amino-6-cyclopropylamino-9H-purin-9-yl]methyl}cyclopropyl)oxy]methylphosphonate(Compound 50)

The compound prepared in Example 7 was reacted according to the sameprocedure as Example 47 to give the title compound.

¹H NMR (CDCl₃) δ 0.60 (br.s, 2H), 0.84 (br.s, 4H), 1.01 (m, 2H), 2.98(br.s, 1H), 4.05 (d, 2H), 4.14 (m, 4H), 4.70 (br.s, 2H), 5.67 (br.s,1H), 7.60 (s, 1H)

ESI: 519, [M+H]+, C17H21F6N6O4P

Example 52 Synthesis of({1-[(2-amino-9H-purin-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonicacid (Compound 98)

The 6-chloroguanine derivative prepared in Preparation 12 was reactedaccording to the same procedure as Example 5 to give the title compound.

¹H NMR (MeOH-d4) δ 0.68 (t, 1H), 1.13 (m, 1H), 1.21 (d, 3H), 1.42 (t,1H), 3.84 (t, 1H), 3.97 (t, 1H), 4.40 (d, 1H), 4.66 (d, 1H), 8.63 (s,1H), 8.73 (s, 1H)

ESI: 314 (M+1)⁺, C11H16N5O4P

The compound of the present invention exhibits a potent pharmacologicaleffect to a hepatitis B cell line, HepG2.2.15, and a transgenic mouse,widely used for development of a therapeutic agent against hepatitis B,when intravenously or orally administered. The experimental proceduresand results are described below.

Experiment 1

Measurement and Analysis of Inhibition Effect Against Hepatitis B Virus(HBV)

(1) Cell Culture and Treatment with Drugs

HepG2.2.15 cell (M. A Shells et al., P.N.A.S. 84, 1005(1987)), ahepatocarcinoma cell line producing hepatitis B virus, was cultured inDMEM medium (GIBCO BRL, #430-2200) containing 10% FBS (Fetus bovineserum, GIBCO BRL, #16000-044), 1% ABAM (Antibiotic-Antimycotic, GIBCOBRL, #16000-028) and 400 μg/ml of geneticin (Sigma, #G-9516) in a T-75flask under the conditions of 5% CO₂ incubator and 37° C. by dividing ina ratio of 1:3 at an interval of 3 days. The cells were distributed intoa 96-well plate in the amount of 4×10⁴/well and then when 80-90% of celldensity was achieved, the old medium was changed with 200 μl of DMEMmedium containing 2% FBS, 1% ABAM and 400 μg/ml of geneticin. The drugsolution was sequentially diluted five-fold each time, from 100 M to0.16 M. In order to minimize an experimental error, each treatment wasrepeated 2-3 times for the respective drugs. The medium was changedevery two days. On 10 days after the treatment with drug, 100 μl of themedium was collected and the degree of inhibition of viral replicationby drugs was determined through quantitative PCR (Polymerase ChainReaction).

(2) Determination of Cytotoxicity

After 100 μl of the medium was collected on 10th day from the treatmentwith drug, 7.5 mg/ml of MTT (Thiazolyl Blue Tetrazolium Broide, Amresco,#0793-5G) solution was added to each well in the amount of 30 μl/welland each cell was cultured for 2 hours in a 5% CO₂ incubator at 37° C.The solution was discarded, and an isopropanol solution containing 10%Triton X-100 and 0.4 μl of c-HCl was added to each well in the amount of120 μl/well. The cells thus dyed were transferred to the isopropanolsolution by shaking for 2 hours. Absorbance at 540 nm was measured byElisa Reader.

(3) PCR Estimation of Inhibition Effect on Hepatitis B Virus Replication

The degree of inhibition by drugs on the replication of hepatitis Bvirus was determined using the cell culture solution collected on 10thday after the treatment with the drug. The cell culture solution treatedwith each drug was diluted ten-fold with distilled water and subjectedto a pretreatment to destroy the cells by heating them for 15 minutes at95° C. For the PCR amplification of the gene fragment of about 320 bp,the 2001-base position that is conserved in all sub-strain of hepatitisB virus and 2319-base position that is between the core antigen gene andpolymerase gene were used as 5′-end and 3′-end primer, respectively.Then, the amount of genomic DNA of hepatitis B virus was quantified, andthe inhibitory effect by drugs on the replication of hepatitis B viruswas determined on the basis thereof.

First, the cell culture solution of hepatitis B virus that was nottreated with drug was sequentially diluted and amplified through thePCR. The amplified DNA was subjected to electrophoresis on 2% agarosegel and stained with ethidium bromide (EtBr) to be analyzed by IS-1000(Innotech Scientific Corporation) Digital Imaging System. Analysis ofthe cell culture solution treated with drug was then carried out usingthe dilution fold in the range where linearity is maintained. The DNAobtained from the group treated with drug was amplified through the samePCR method, subjected to electrophoresis on 2% agarose gel, stained withethidium bromide, and analyzed by IS-1000. The degree of inhibition bydrugs in the viral replication was quantified by calculating the ratioof test group to control group. Table 8 summarizes the inhibitory effect(pharmaceutical activity and toxicity) of the typical compounds of thepresent invention.

TABLE 8 COM. NO. EC₅₀ (μM) in HBV PMEA 5.0 (Comparative Compound) 1 >1.0  3 >0.5  5 >0.1 10 >0.08 95 >0.5 97 >0.05

As can be seen from the results of Table 8, the compound according tothe present invention exhibits 4 to 10-fold greater activity than thecomparative compound PMEA that is on Phase III in clinical trials.

Experiment 2

Pharmacological Test on Transgenic Mouse (T/G Mouse)

The compounds were administered via subcutaneous and oral routes in thefollowing animal test.

The test compounds were administered to 4-5 weeks old HBV transgenicmice, which were obtained from FVB strain mice according to a methoddescribed in a reference (see, Jone D. Morrey, Kevin W. Bailey, Brent E.Korba, Robert W. Sidwell, “Utilization of transgenic mice replicatinghigh levels of hepatitis B virus for antiviral evaluation of lamivudine”Antiviral research, 1999, 42, 97-108), subcutaneously for 9 days in theamount of 10 mg/kg/day and orally for 9 days in the amount of 10, 2 and0.4 mg/kg/day, once a day, respectively (the same number of males andfemales were used). Blood was collected from the tail of the mouse and 5μl of serum was obtained. To this serum was added 15 ml of Genereleasersol, which was then pretreated in different temperatures. HBV DNA wastaken from the pretreated solution. The DNA was amplified by the PCR(Polymerase Chain Reaction) in the presence of 4 μl of 10× buffer(Perkin Elmer), 0.8 μl of 10 mM dNTP, 500 ng of the same HBV primers asused in Experiment 1, 2,125 mM of MgCl₂, DMSO and Taq polymerase. Theamount of HBV DNA was analyzed by electrophoresis in order to evaluate apharmacological effect of the compound of the present invention. Theresults are described in the following Table 9. In the following Table9, ┌mice showing pharmacological effect┘ means the mice whose blood doesnot contain HBV DNA.

TABLE 9 Amount COM. NO. (mg/kg/day) Result* Administration 23 10 4/4subcutaneous 66 10 4/4 subcutaneous 97 10 4/4 subcutaneous 95 10 3/4subcutaneous 98 10 4/4 subcutaneous PMEA dipivoxil 2 1/3 oral PMEAdipivoxil 0.4 1/6 oral 10 2 4/4 oral 10 0.4 5/6 oral *The result means┌number of mice showing pharmacological effect/number of total mice┘

As can be seen in the above Table 9, the compound of the presentinvention shows a potent hepatitis B therapeutic effect in the testedanimals when orally or subcutaneously administered. Particularly, sincethe compound of the present invention is superior to the comparativecompound PMEA, which is on Phase III in clinical trials, it is expectedthat the compound of the present invention may be used very effectivelyfor the treatment of hepatitis B.

1. A phosphonate compound represented by the following formula (2):

in which

 represents single bond or double bond, R¹, R², R³, R⁷, and R⁸independently of one another represent hydrogen, halogen, hydroxyl,amino, C₁-C₇-alkyl, C₂-C₆-alkenyl, C₁-C₅-alkylamino, C₁-C₅-aminoalkyl,or C₁-C₅-alkoxy, R⁴ and R⁵ independently of one another representhydrogen, or represent C₁-C₄-alkyl optionally substituted by one or moresubstituents selected from the group consisting of halogen,C₁-C₄-alkoxy, phenoxy, C₇-C₁₀-phenylalkoxy and C₂-C₅-acyloxy, whereinC₂-C₅-acyloxy is RC(O)O— and R is C₂-C₅-alkyl, or represent C₁-C₇-acyl,wherein C₁-C₇-acyl is RC(O)— and R is C₁-C₇-alkyl, C₆-C₁₂-aryl oroptionally substituted carbamoyl, or represent —(CH₂)m-OC(═O)—R⁶ whereinm denotes an integer of 1 to 12 and R⁶ represents C₁-C₁₂-alkyl,C₂-C₇-alkenyl, C₁-C₅-alkoxy, C₁-C₇-alkylamino, di(C₁-C₇-alkyl)amino,C₃-C₆-cycloalkyl, or 3 to 6-membered heterocycle having 1 or 2 heteroatoms selected from a group consisting of nitrogen and oxygen, Yrepresents —O—, —S—, —CH(Z)—, ═C(Z)—, —N(Z)—, ═N—, —SiH(Z)—, or ═Si(Z)—,wherein Z represents hydrogen, hydroxyl or halogen, or representsC₁-C₇-alkyl, C₁-C₅-alkoxy, allyl, hydroxy-C₁-C₇-alkyl, C₁-C₇-aminoalkylor phenyl, and L represents a leaving group.